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Abstract Background Reflux esophagitis (RE) is a disease in which inflammation of the esophageal mucosa owing to the reflux of gastric contents into the esophagus results in cytokine damage. Britannilactone 1-O-acetate (Brt) has anti-inflammatory effects, significantly inhibiting the activation of the NLRP3 inflammasome, leading to a decrease in inflammatory factors including IL-1 β, IL-6, and TNF-α. However, the mechanism underlying its protective effect against RE-induced esophageal injury remains unclear. In the present study, we investigated the protective mechanism of TRIM31 against NLRP3 ubiquitination-induced RE both in vivo and in vitro. Methods A model of RE was established in vivo in rats by the method of “4.2 mm pyloric clamp + 2/3 fundoplication”. In vitro, the mod was constructed by using HET-1A (esophageal epithelial cells) and exposing the cells to acid, bile salts, and acidic bile salts. The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was used to screen the concentration of administered drugs, and the viability of HET-1A cells in each group. HE staining was used to assess the degree of pathological damage in esophageal tissues. Toluidine blue staining was used to detect whether the protective function of the esophageal epithelial barrier was damaged and restored. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL-1 β, IL-6, and TNF-α factors in serum. Immunohistochemistry (IHC) was used to detect the expression level of NLRP3 in esophageal tissues. The molecular docking and Co-immunoprecipitation assay (Co-IP assay) were used to detect the TRIM31 interacts with NLRP3. Western blotting detected the Claudin-4, Claudin-5, The G-protein-coupled receptor calcium-sensitive receptor (CaSR), NLRP3, TRIM31, ASC, C-Caspase1, and Caspase1 protein expression levels. Results Brt could alleviate RE inflammatory responses by modulating serum levels of IL-1 β, IL-6, and TNF-α. It also activated the expression of NLRP3, ASC, Caspase 1, and C-Caspase-1 in HET-1A cells. Brt also attenuated TRIM31/NLRP3-induced pathological injury in rats with RE through a molecular mechanism consistent with the in vitro results. Conclusions Brt promotes the ubiquitination of NLRP3 through TRIM31 and attenuates esophageal epithelial damage induced by RE caused by acidic bile salt exposure. This study provides valuable insights into the mechanism of action of Brt in the treatment of RE and highlights its promising application in the prevention of NLRP3 inflammatory vesicle-associated inflammatory pathological injury. Graphical Abstract

Abstract Most TRIM family members characterized by the E3-ubiquitin ligases, participate in ubiquitination and tumorigenesis. While there is a dearth of a comprehensive investigation for the entire family in gastric cancer (GC). By combining the TCGA and GEO databases, common TRIM family members (TRIMs) were obtained to investigate gene expression, gene mutations, and clinical prognosis. On the basis of TRIMs, a consensus clustering analysis was conducted, and a risk assessment system and prognostic model were developed. Particularly, TRIM31 with clinical prognostic and diagnostic value was chosen for single-gene bioinformatics analysis, in vitro experimental validation, and immunohistochemical analysis of clinical tissue microarrays. The combined dataset consisted of 66 TRIMs, of which 52 were differentially expressed and 43 were differentially prognostic. Significant survival differences existed between the gene clusters obtained by consensus clustering analysis. Using 4 differentially expressed genes identified by multivariate Cox regression and LASSO regression, a risk scoring system was developed. Higher risk scores were associated with a poorer prognosis, suppressive immune cell infiltration, and drug resistance. Transcriptomic data and clinical sample tissue microarrays confirmed that TRIM31 was highly expressed in GC and associated with a poor prognosis. Pathway enrichment analysis, cell migration and colony formation assay, EdU assay, reactive oxygen species (ROS) assay, and mitochondrial membrane potential assay revealed that TRIM31 may be implicated in cell cycle regulation and oxidative stress-related pathways, contribute to gastric carcinogenesis. This study investigated the whole functional and expression profile and a risk score system based on the TRIM family in GC. Further investigation centered around TRIM31 offers insight into the underlying mechanisms of action exhibited by other members of its family in the context of GC.

Background: Reflux esophagitis (RE) is a disease in which inflammation of the esophageal mucosa owing to the reflux of gastric contents into the esophagus results in cytokine damage. Britannilactone 1-O-acetate (Brt) has anti-inflammatory effects, significantly inhibiting the activation of the NLRP3 inflammasome, leading to a decrease in inflammatory factors including IL-1 β, IL-6, and TNF-α. However, the mechanism underlying its protective effect against RE-induced esophageal injury remains unclear. In the present study, we investigated the protective mechanism of TRIM31 against NLRP3 ubiquitination-induced RE both in vivo and in vitro. Methods: A model of RE was established in vivo in rats by the method of "4.2 mm pyloric clamp + 2/3 fundoplication". In vitro, the mod was constructed by using HET-1A (esophageal epithelial cells) and exposing the cells to acid, bile salts, and acidic bile salts. The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was used to screen the concentration of administered drugs, and the viability of HET-1A cells in each group. HE staining was used to assess the degree of pathological damage in esophageal tissues. Toluidine blue staining was used to detect whether the protective function of the esophageal epithelial barrier was damaged and restored. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL-1 β, IL-6, and TNF-α factors in serum. Immunohistochemistry (IHC) was used to detect the expression level of NLRP3 in esophageal tissues. The molecular docking and Co-immunoprecipitation assay (Co-IP assay) were used to detect the TRIM31 interacts with NLRP3. Western blotting detected the Claudin-4, Claudin-5, The G-protein-coupled receptor calcium-sensitive receptor (CaSR), NLRP3, TRIM31, ASC, C-Caspase1, and Caspase1 protein expression levels. Results: Brt could alleviate RE inflammatory responses by modulating serum levels of IL-1 β, IL-6, and TNF-α. It also activated the expression of NLRP3, ASC, Caspase 1, and C-Caspase-1 in HET-1A cells. Brt also attenuated TRIM31/NLRP3-induced pathological injury in rats with RE through a molecular mechanism consistent with the in vitro results. Conclusions: Brt promotes the ubiquitination of NLRP3 through TRIM31 and attenuates esophageal epithelial damage induced by RE caused by acidic bile salt exposure. This study provides valuable insights into the mechanism of action of Brt in the treatment of RE and highlights its promising application in the prevention of NLRP3 inflammatory vesicle-associated inflammatory pathological injury. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases and is known to induce endoplasmic reticulum (ER) stress, which alters cellular homeostasis and metabolic processes. While ER stress is implicated in HCV-related diseases, its precise role remains unclear. This study identifies fibroblast growth factor 21 (FGF21) as a key host factor significantly upregulated by HCV infection. Mechanistic analyses reveal that the activation of the FGF21 promoter by HCV is primarily mediated by the transcription factor ATF4, which is upregulated through the phosphorylation of eIF2α induced by ER stress. Additionally, CREBH activation further enhances ATF4 expression, contributing to increased FGF21 levels. TRIB3, upregulated by ATF4, acts as a negative regulator of FGF21 expression. The study also identifies FGF21-dependent upregulation of SOCS2 and TRIM31 in HCV-infected cells. SOCS2 contributes to the suppression of type 1 interferon signaling, aiding viral persistence, while TRIM31 promotes the degradation of the tumor suppressor protein TSC, activating themTORC1 pathway and potentially promoting liver cell proliferation. These findings suggest that FGF21 upregulation in HCV-infected cells may play a role in both immune response regulation and cell proliferation, contributing to sustained viral infection and disease progression. [ABSTRACT FROM AUTHOR]

Most TRIM family members characterized by the E3-ubiquitin ligases, participate in ubiquitination and tumorigenesis. While there is a dearth of a comprehensive investigation for the entire family in gastric cancer (GC). By combining the TCGA and GEO databases, common TRIM family members (TRIMs) were obtained to investigate gene expression, gene mutations, and clinical prognosis. On the basis of TRIMs, a consensus clustering analysis was conducted, and a risk assessment system and prognostic model were developed. Particularly, TRIM31 with clinical prognostic and diagnostic value was chosen for single-gene bioinformatics analysis, in vitro experimental validation, and immunohistochemical analysis of clinical tissue microarrays. The combined dataset consisted of 66 TRIMs, of which 52 were differentially expressed and 43 were differentially prognostic. Significant survival differences existed between the gene clusters obtained by consensus clustering analysis. Using 4 differentially expressed genes identified by multivariate Cox regression and LASSO regression, a risk scoring system was developed. Higher risk scores were associated with a poorer prognosis, suppressive immune cell infiltration, and drug resistance. Transcriptomic data and clinical sample tissue microarrays confirmed that TRIM31 was highly expressed in GC and associated with a poor prognosis. Pathway enrichment analysis, cell migration and colony formation assay, EdU assay, reactive oxygen species (ROS) assay, and mitochondrial membrane potential assay revealed that TRIM31 may be implicated in cell cycle regulation and oxidative stress-related pathways, contribute to gastric carcinogenesis. This study investigated the whole functional and expression profile and a risk score system based on the TRIM family in GC. Further investigation centered around TRIM31 offers insight into the underlying mechanisms of action exhibited by other members of its family in the context of GC. [ABSTRACT FROM AUTHOR]

Ubiquitination is a key mechanism for post-translational protein modification, affecting protein localization, metabolism, degradation and various cellular physiological processes. Dysregulation of ubiquitination is associated with the pathogenesis of various diseases, such as tumors and cardiovascular diseases, making it a primary area of interest in biochemical research and drug development endeavors. E3 ubiquitin ligases play a pivotal role in modulating the ubiquitination of substrate proteins through their unique recognition functions. TRIM31, a member of the TRIM family of E3 ubiquitin ligases, is aberrantly expressed in different pathophysiological conditions. The biological function of TRIM31 is associated with the occurrence and development of diverse diseases. TRIM31 has been demonstrated to inhibit inflammation by promoting ubiquitin-proteasome-mediated degradation of the sensing protein NLRP3 in the inflammasome. TRIM31 mediates ubiquitination of MAVS, inducing the formation of prion-like aggregates, and triggering innate antiviral immune responses. TRIM31 is also implicated in tumor pathophysiology through its ability to promote ubiquitination of the tumor suppressor protein p53. These findings indicate that TRIM31 is a potential therapeutic target, and subsequent in-depth research of TRIM31 is anticipated to provide information on its clinical application in therapy.

The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression.

Abstract Background The NLRP3 inflammasome activation is the molecular basis of Helicobacter pylori (Hp)-associated gastritis. Tripartite motif (TRIM) 31 is involved in diverse pathological events. However, whether TRIM31 plays a role in the activation of NLRP3 inflammasome in Hp infection is not clarified. Methods A mouse model of chronic Hp infection was established, and the gastric tissues were subjected to the polymerase chain reaction, western blotting, histopathological analysis, and RNA sequencing. The mitochondrial membrane potential and ROS in the human gastric epithelium GES-1 cells with or without Hp infection were measured by flow cytometry. GES-1 cells with or without TRIM31 knockdown were transfected with mCherry-EGFP-LC3 adenovirus. After rapamycin and bafilomycin A1 stimulation, autophagy flux in the above primed GES-1 cells was assessed by laser confocal microscope. Lysosomal acidification and expression levels of cathepsin B and cathepsin D in GES-1 cells with Hp infection were measured. Results NLRP3 inflammasome was activated in the gastric tissues of mice with chronic Hp infection in vivo and the GES-1 cells with Hp infection in vitro. TRIM31 was downregulated in Hp infection. TRIM31 negatively regulated the NLRP3 inflammasome activation. Enhanced ROS, impaired autophagy flux, and decreased expression of lysosomal cathepsin B and cathepsin D were observed in TRIM31-deficient GES-1 cells with Hp infection. In turn, inhibition of ROS led to the decreased expression of NLRP3 inflammasome. Conclusions Together, our data identified that TRIM31 negatively regulated the activation of NLRP3 inflammasome in Hp-associated gastritis by affecting ROS and autophagy of gastric epithelial cells. Video abstract

To understand the molecular mechanisms that mediate the anti-hepatitis B virus (HBV) effect of interferon (IFN) therapy, we conduct high-throughput bimolecular fluorescence complementation screening to identify potential physical interactions between the HBx protein and 145 IFN-stimulated genes (ISGs). Seven HBx-interacting ISGs have consistent and significant inhibitory effects on HBV replication, among which TRIM5γ suppresses HBV replication by promoting K48-linked ubiquitination and degradation of the HBx protein on the K95 ubiquitin site. The B-Box domain of TRIM5γ under overexpression conditions is sufficient to trigger HBx degradation and is responsible both for interacting with HBx and recruiting TRIM31, which is an ubiquitin ligase that triggers HBx ubiquitination. High expression levels of TRIM5γ in IFN-α-treated HBV patients might indicate a better therapeutic effect. Thus, our studies identify a crucial role for TRIM5γ and TRIM31 in promoting HBx degradation, which may facilitate the development of therapeutic agents for the treatment of patients with IFN-resistant HBV infection.

The regulation of protein kinase B (AKT) phosphorylation by Tripartite motif-containing protein 31 (TRIM31) is implicated as an essential mechanism in the progression of many malignant tumors. Nevertheless, the function of the TRIM31/ AKT pathway in oral squamous cell carcinoma (OSCC) remains elusive. Here, immunohistochemistry analysis of human OSCC tissue microarrays indicated significantly higher levels of TRIM31 and phosphorylated AKT (p-AKT) in OSCC tumors than in adjacent tissue samples. Also, we detected a positive association between TRIM31 expression and clinical OSCC development. In in vitro studies, TRIM31 knockdown severely impaired OSCC cell growth, invasion, and migration. By contrast, TRIM31 overexpression improved these cell behaviors, while subsequent AKT inhibition abrogated the effect. In vivo tumorigenesis experiments using nude mice also validated the effects of TRIM31/AKT signaling in tumor growth. Furthermore, TRIM31 upregulation facilitated glucose uptake, as well as lactate and adenosine triphosphate production of OSCC cells, while such positive effects on glycolysis and malignant cell phenotypes were reversed by treatment with AKT or glycolysis inhibitors. In conclusion, TRIM31 may improve OSCC progression by enhancing AKT phosphorylation and subsequent glycolysis. Hence, TRIM31 has the potential as a treatment target in OSCC. [ABSTRACT FROM AUTHOR]

Background: The NLRP3 inflammasome activation is the molecular basis of Helicobacter pylori (Hp)-associated gastritis. Tripartite motif (TRIM) 31 is involved in diverse pathological events. However, whether TRIM31 plays a role in the activation of NLRP3 inflammasome in Hp infection is not clarified. Methods: A mouse model of chronic Hp infection was established, and the gastric tissues were subjected to the polymerase chain reaction, western blotting, histopathological analysis, and RNA sequencing. The mitochondrial membrane potential and ROS in the human gastric epithelium GES-1 cells with or without Hp infection were measured by flow cytometry. GES-1 cells with or without TRIM31 knockdown were transfected with mCherry-EGFP-LC3 adenovirus. After rapamycin and bafilomycin A1 stimulation, autophagy flux in the above primed GES-1 cells was assessed by laser confocal microscope. Lysosomal acidification and expression levels of cathepsin B and cathepsin D in GES-1 cells with Hp infection were measured. Results: NLRP3 inflammasome was activated in the gastric tissues of mice with chronic Hp infection in vivo and the GES-1 cells with Hp infection in vitro. TRIM31 was downregulated in Hp infection. TRIM31 negatively regulated the NLRP3 inflammasome activation. Enhanced ROS, impaired autophagy flux, and decreased expression of lysosomal cathepsin B and cathepsin D were observed in TRIM31-deficient GES-1 cells with Hp infection. In turn, inhibition of ROS led to the decreased expression of NLRP3 inflammasome. Conclusions: Together, our data identified that TRIM31 negatively regulated the activation of NLRP3 inflammasome in Hp-associated gastritis by affecting ROS and autophagy of gastric epithelial cells. BaPkEPhQjKRgDMqnjfdJ-V Video abstract [ABSTRACT FROM AUTHOR]

Tripartite motif (TRIM) 31 is a new member of the TRIM family and functions as an E3 ubiquitin ligase. Abnormal TRIM31 expression leads to a variety of pathological conditions, such as cancer, innate immunity diseases, sepsisinduced myocardial dysfunction, cerebral ischemic injury, nonalcoholic fatty liver disease and hypertensive nephropathy. In this review, we comprehensively overview the structure, expression and regulation of TRIM31 in cancer. Moreover, we discuss the dual role of TRIM31 in human cancer, and this dual role may be linked to its involvement in the selective regulation of several pivotal cellular signaling pathways: the p53 tumor suppressor, mTORC1, PI3KAKT, NF-&#k954;B and Wnt/β-catenin pathways. In addition, we also discuss the emerging role of TRIM31 in innate immunity, autophagy and its growing sphere of influence across multiple human pathologies. Finally, a better understanding of the dual role of TRIM31 in cancer may provide new therapeutic strategies aimed at inhibiting the cancer-promoting effects of TRIM31 without affecting its tumor suppressor effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • Trim31 expression was decreased in the lung tissues of asthmatic mice. • Trim31 deficiency exacerbated airway inflammation in asthmatic mice. • Trim31 overexpression inhibited inflammatory response in airway epithelial cells. • Trim31 deficiency amplified NLRP3 inflammasome activation in asthma. Tripartite motif (Trim) 31 is important for numerous inflammatory diseases. However, whether Trim31 regulates airway inflammation in asthma remains undetermined. The present work explored the role of Trim31 in airway inflammation in asthmatic mice established by ovalbumin (OVA) stimulation. Trim31 expression was markedly downregulated in the lungs of asthmatic mice. Compared with wild-type (WT) mice, Trim31-/- mice showed more severe pathological changes accompanied by increased inflammatory cell infiltration after OVA induction. House dust mite (HDM) stimulation evoked airway epithelial cell injury and inflammation, which were exacerbated by Trim31 silencing or attenuated by Trim31 overexpression. Further examination revealed that Trim31 deficiency exacerbated the activation of the NLRP3 inflammasome in OVA-induced asthmatic mice and HDM-stimulated airway epithelial cells. The inhibition of NLRP3 markedly diminished the Trim31 silencing-mediated enhancement of HDM-induced injury and inflammation in airway epithelial cells. In conclusion, this work demonstrates that Trim31 acts as a crucial mediator of airway inflammation in asthma. Trim31 deficiency may contribute to the progression of asthma by increasing NLRP3 inflammasome activation, suggesting that Trim31 is a potential therapeutic target for asthma. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression. • CUMS activated NLRP3 inflammasome in PFC and upregulated TRIM31 protein expression. • MDZXYS reversed CUMS-induced depression-like behaviors and ameliorated neuronal damage in rats. • MDZXYS inhibited NLRP3 inflammasome activation and promoted NLRP3 and TRIM31 co-localization in PFC. [ABSTRACT FROM AUTHOR]

Ubiquitination is a key mechanism for post-translational protein modification, affecting protein localization, metabolism, degradation and various cellular physiological processes. Dysregulation of ubiquitination is associated with the pathogenesis of various diseases, such as tumors and cardiovascular diseases, making it a primary area of interest in biochemical research and drug development endeavors. E3 ubiquitin ligases play a pivotal role in modulating the ubiquitination of substrate proteins through their unique recognition functions. TRIM31, a member of the TRIM family of E3 ubiquitin ligases, is aberrantly expressed in different pathophysiological conditions. The biological function of TRIM31 is associated with the occurrence and development of diverse diseases. TRIM31 has been demonstrated to inhibit inflammation by promoting ubiquitin-proteasome-mediated degradation of the sensing protein NLRP3 in the inflammasome. TRIM31 mediates ubiquitination of MAVS, inducing the formation of prion-like aggregates, and triggering innate antiviral immune responses. TRIM31 is also implicated in tumor pathophysiology through its ability to promote ubiquitination of the tumor suppressor protein p53. These findings indicate that TRIM31 is a potential therapeutic target, and subsequent in-depth research of TRIM31 is anticipated to provide information on its clinical application in therapy. [Display omitted] • The E3 ligase TRIM31 is a potential therapeutic target for various diseases. • TRIM31 regulates inflammation and innate immunity through its E3 ligase activity. • The E3 ligase TRIM31 has a dual role as a tumor suppressor or oncogene in different tumors. • The challenges and prospective advances regarding TRIM31 as a therapeutic target are presented in this paper. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases and is known to induce endoplasmic reticulum (ER) stress, which alters cellular homeostasis and metabolic processes. While ER stress is implicated in HCV-related diseases, its precise role remains unclear. This study identifies fibroblast growth factor 21 (FGF21) as a key host factor significantly upregulated by HCV infection. Mechanistic analyses reveal that the activation of the FGF21 promoter by HCV is primarily mediated by the transcription factor ATF4, which is upregulated through the phosphorylation of eIF2α induced by ER stress. Additionally, CREBH activation further enhances ATF4 expression, contributing to increased FGF21 levels. TRIB3, upregulated by ATF4, acts as a negative regulator of FGF21 expression. The study also identifies FGF21-dependent upregulation of SOCS2 and TRIM31 in HCV-infected cells. SOCS2 contributes to the suppression of type 1 interferon signaling, aiding viral persistence, while TRIM31 promotes the degradation of the tumor suppressor protein TSC, activating the mTORC1 pathway and potentially promoting liver cell proliferation. These findings suggest that FGF21 upregulation in HCV-infected cells may play a role in both immune response regulation and cell proliferation, contributing to sustained viral infection and disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Ito, Sakai, Liu, Ohta, Saito, Nakashima, Satoh, Konno and Suzuki.)

Tripartite motif (TRIM) 31 has been implicated in diverse biological and pathological conditions. However, whether TRIM31 plays a role in ischemic stroke progression is not clarified. Here we demonstrated that TRIM31 was significantly downregulated in the ischemic brain and the deficiency of TRIM31 alleviated brain injury induced by middle cerebral artery occlusion by reducing reactive oxygen species production and maintaining mitochondrial homeostasis. Mechanistically, we found that TRIM31 is an E3 ubiquitin ligase for TP53-induced glycolysis and apoptosis regulator (TIGAR), which confers protection against brain ischemia by increasing the pentose phosphate pathway flux and preserving mitochondria function. TRIM31 interacted with TIGAR and promoted the polyubiquitination of TIGAR, consequently facilitated its degradation in a proteasome-dependent pathway. Furthermore, TIGAR knockdown effectively abolished the protective effect of TRIM31 deficiency after cerebral ischemia. In conclusion, we identified that TRIM31 was a novel E3 ubiquitin ligase for TIGAR, played a critical role in regulating its protein level, and subsequently involved in the ischemic brain injury, suggesting TRIM31 as a potential therapeutic target for ischemic stroke.

NOD‐like receptor protein 3 (NLRP3) is associated with age‐related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells serve as the immune defense of macula, and their dysfunction causes clinically relevant changes in AMD. In the present study, oxidized low‐density lipoprotein (ox‐LDL) activated the NLRP3 inflammasome in human RPE cell line ARPE‐19. Our data showed that the expression of NLRP3, interleukin‐1β (IL‐1β), and caspase‐1 and the release of IL‐1β in ARPE‐19 cells were substantially increased by ox‐LDL, whereas the addition of NLRP3 inhibitor INF39 dose‐dependently reversed the effect of ox‐LDL. Overexpression of tripartite motif‐containing protein 31 (TRIM31) also suppressed the effect of ox‐LDL in ARPE‐19 cells. TRIM31 knockdown had similar effects with ox‐LDL but INF39 could block the effect of TRIM31 knockdown. Moreover, TRIM31 could interact with NLRP3 in ARPE‐19 cells. Overexpression of TRIM31 increased NLRP3 ubiquitination. In conclusion, the results propose that TRIM31 could enhance NLRP3 ubiquitination, therefore inhibiting NLRP3 inflammasome and pyroptosis in human RPE cells. [ABSTRACT FROM AUTHOR]

Apical periodontitis (AP) is an inflammatory disease caused by bacteria infection and is regarded as a common disease in the world. In the progression of AP, the function of nucleotide-binding oligomerization, leucine-rich repeat and pyrin domain domains-containing protein 3 (NLRP3) inflammasome has been revealed. Although tripartite motif 31 (TRIM31) has been suggested to regulate many chronic inflammations by mediating NLRP3 inflammasome, such mechanism in AP remains unclear. In this study, co-treatment of human periodontal ligament fibroblasts (HPDLFs) with lipopolysaccharides (LPS) and adenosine triphosphate (ATP) were conducted to establish AP cell model. ELISA assay was used to measure the concentration of secretive interleukin 1 beta (IL-1β). In addition, the expression levels of NLRP3 after TRIM31 up- or down-regulation were detected by real-time PCR and western blot. Immunoprecipitation was used to explore the interaction between TRIM31 and NLRP3. We found that co-treatment with LPS and ATP increased the secretion of IL-1β and expression of NLRP3 in HPDLFs, while TRIM31 overexpression could reverse these effects caused by LPS and ATP. Furthermore, the interaction between TRIM31 and NLRP3 was observed, and TRIM31 was found to promote the ubiquitination of NLRP3. TRIM31 may alleviate IL-1ß secretion caused by LPS and ATP via promoting the ubiquitination of NLRP3 and may exert an influence on the development of AP. [ABSTRACT FROM AUTHOR]

Purpose: Biomarkers that predict radiosensitivity are essential for personalized radiotherapy. We performed microarray analysis for rectal cancer patients between those with good response and poor response to preoperative radiotherapy and found that patients with lower expression of tripartite motif-containing protein 31 (TRIM31) showed a better response. In this study, we confirmed the effects of TRIM31 on radiosensitivity by knockdown of TRIM31 in colorectal cancer cells. Methods and materials: Human colorectal cancer cell lines HT-29 and SW480, which are TRIM31 stably knocked-down, were used for analysis. We studied the level of DNA damage and the change of relative proteins after irradiation in TRIM31-knockdown cells. Flow cytometry was used to test for apoptosis, cell cycle stage, and reactive oxygen species (ROS) levels after irradiation. Cell survival was measured by cloning assay. Proteins related to DNA damage were evaluated by Western blotting. Results: The percentage of apoptotic cells and the levels of ROS were elevated, and the survival fraction was reduced in TRIM31-knockdown cells. The expression levels of the DNA damage proteins phosphorylated ataxia-telangiectasia mutation (P-ATM), DNA protein kinases (DNA-PKs), and γ-H2AX were higher in TRIM31-knockdown cells. Conclusion: Knockdown of TRIM31 increases DNA damage and radiosensitivity in colorectal cancer cells. [ABSTRACT FROM AUTHOR]

This study is intended to investigate the role of Tripartite Motif (TRIM) 31 in glioma. Immunohistochemistry and western blot analysis showed that TRIM31 was overexpressed in high-grade glioma tissues. Univariate survival analysis indicated that high expression of TRIM31 was related to short survival time of glioma patients. Multivariate survival analysis demonstrated that TRIM31 was an independent prognostic factor for glioma patients. In addition, through the experiments on glioma cell lines, we found that after silencing or overexpressing TRIM31 expression, the proliferation, invasion and migration of glioma cells could be downregulated or upregulated through Akt signaling pathway. In short, our study suggests that TRIM31 may be an effective target for glioma intervention. [ABSTRACT FROM AUTHOR]

Background: Glioma is the most lethal primary brain tumor, the survival rate still isn't improved in the past decades. It's essential to study the regulatory mechanism of glioma progression, hoping to find new therapy targets or methods. The family of tripartite motif (TRIM) containing proteins are E3 ubiquitination ligases, which play critical role in various tumor progression. Methods: Cell proliferation and invasion were analyzed by colony formation assay, soft agar growth assay, BrdU incorporation assay and transwell invasion assay. Luciferase reporter analysis was used to analyze NF-κB pathway activity. Results: We found TRIM31 was upregulated in glioma cells and tissues, its overexpression significantly promoted glioma cell proliferation and invasion, while its knockdown significantly inhibited glioma cell proliferation and invasion. Mechanism analysis found TRIM31 promoted NF-κB pathway activity and increased its targets expression. NF-κB inhibition reversed the phenotype caused by TRIM31, confirming TRIM31 promoted glioma progression through activating NF-κB pathway. Using clinical specimens found TRIM31 expression was positively correlative with NF-κB activity. Conclusion: This study found TRIM31 promoted glioma proliferation and invasion through activating NF-κB activity. [ABSTRACT FROM AUTHOR]

Nickel compounds are widely used in industries and daily life as important industrial products. Long-term exposure to nickel compounds has been associated with increased incidence and poor prognosis of lung cancer. However, the molecular mechanism by which exposure to nickel compounds induces the malignant phenotype of lung cancer cells remains unclear. In this study, we confirmed that nickel chloride (NiCl 2) exposure promotes invasion and metastasis through IL - 6 / STAT3 both in vitro and vivo. Mechanistically, we found that NiCl 2 mediated the transcriptional regulation of E3 ubiquitin ligase TRIM31 by SATAT3 phosphorylation, and promoted its up-regulation. Overexpression TRIM31 is an independent risk factor for lung cancer patients, and it promotes the invasion and metastasis of lung cancer cells. In addition, E3 ubiquitination ligase TRIM31 binds to its substrate TP53 protein in the RING region and accelerates TP53 protein ubiquitination and degradation. Functional recovery experiments showed that NiCl 2 exposure promotes the invasion and metastasis ability of lung cancer and ubiquitination-mediated degradation of TP53 protein through the STAT3 / TRIM31 axis. These findings reveal the role and mechanism of NiCl 2 in lung cancer progression, indicating that STAT3 and TRIM31 may be promising targets for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase of the tripartite motif family, plays an important role in the innate immune response. It can reduce the activity of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, little information is about glucose metabolic health of TRIM31-deficient mice, and investigations about gut microbiota in TRIM31-deficient mice is limited. Thus, we aimed to compare glucose metabolic parameters, gut microbiota composition and inflammatory cytokine levels between TRIM31−/− and wild-type (WT) mice, and further investigate whether or not certain gut microbiota taxon correlates with specific metabolic parameters and inflammation cytokines in TRIM31-deficient mice. TRIM31−/− mice showed glucose intolerance and insulin resistance, with a significant difference in gut microbiota composition, characterized by increased abundance of Prevotellaceae and Veillonellaceae. TRIM31−/− mice with impaired glucose metabolism was accompanied by elevated serum tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) concentrations, as well as upregulated caecal TNF-α, IL-1β, caspase-1, and NLRP3 expressions. Furthermore, elevated p-IRS-1/IRS-1 protein expression, and decreased Akt Thr308 phosphorylation were observed in TRIM31−/− mice. Prevotellaceae abundance was positively associated with caecal IL-1β mRNA expression, and Veillonellaceae was associated with higher TNF-α mRNA expression and serum insulin concentration. In conclusion, our study is novel in showing that TRIM31 deficiency is associated with impaired glucose metabolism and disrupted gut microbiota in mice. This study contributes to the theoretical foundation on the potential relationship between TRIM31 deficiency and the development of abnormal glucose metabolism.

Tripartite motif (TRIM) 31, a member of the TRIM protein family, contributes to a wide range of biological processes and its altered expression exerts a non-negligible effect on multiple pathological conditions such as immunological disorders and retroviral protective activity. Recently, increasing evidence has demonstrated an important role of TRIM31 in the development of various cancers. However, the role of TRIM31 in gallbladder cancer (GBC) remains unclear. In this study, we showed that TRIM31 was elevated in GBC tissues and cell lines and associated with the clinicopathological features of GBC patients. Down-regulation of TRIM31 suppressed GBC cell proliferation, migration and invasion in vitro as well as inhibited tumor growth and metastasis in vivo. In addition, knockdown of TRIM31 reduced the expression of MMP2, MMP9 and p-Akt. Taken together, these findings indicated that knockdown of TRIM31 suppressed proliferation and invasion of GBC cells and was associated with PI3K/Akt signaling inactivation. Thus, TRIM31 may be a potential therapeutic target for the treatment of GBC. [ABSTRACT FROM AUTHOR]

Anoikis-resistance is an essential feature of cancer cells to obtain successful metastasis, whereas the molecular mechanism involved in this process of hepatocellular carcinoma (HCC) cells is not fully understood. Here we demonstrated that tripartite motif-containing (TRIM) 31, a new member of the TRIM family, was significantly upregulated in the anchorage-deprived HCC cells compared with their attached counterpart. When we blocked TRIM31 expression by its specific interference RNAs, the anoikis-resistance of HCC cells was significantly reversed. We further verified that overactivation of AMPK pathway was responsible for TRIM31-mediated resistance to anoikis of HCC cells; and TRIM31 could directly target p53, the upstream suppressor of AMPK pathway, and mediate K48-linked ubiquitous degradation of p53 in a RING-domain-dependent way. Therefore we demonstrated that TRIM31 promoted anoikis-resistance by targeting p53 for degradation and subsequently overactivating AMPK pathway. Thus our study defined for the first time the role of TRIM31 in the anoikis-resistant process of HCC cells， and it may pave a new avenue for manipulation of metastatic cancer by targeting TRIM31. [ABSTRACT FROM AUTHOR]

Tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase of the tripartite motif family, plays an important role in the innate immune response. It can reduce the activity of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, little information is about glucose metabolic health of TRIM31-deficient mice, and investigations about gut microbiota in TRIM31-deficient mice is limited. Thus, we aimed to compare glucose metabolic parameters, gut microbiota composition and inflammatory cytokine levels between TRIM31-/- and wild-type (WT) mice, and further investigate whether or not certain gut microbiota taxon correlates with specific metabolic parameters and inflammation cytokines in TRIM31-deficient mice. TRIM31-/- mice showed glucose intolerance and insulin resistance, with a significant difference in gut microbiota composition, characterized by increased abundance of Prevotellaceae and Veillonellaceae. TRIM31-/- mice with impaired glucose metabolism was accompanied by elevated serum tumor necrosis factor-a (TNF-a) and interleukin 1b (IL-1b) concentrations, as well as upregulated caecal TNF-a, IL-1b, caspase-1, and NLRP3 expressions. Furthermore, elevated p-IRS-1/IRS-1 protein expression, and decreased Akt Thr308 phosphorylation were observed in TRIM31-/- mice. Prevotellaceae abundance was positively associated with caecal IL-1b mRNA expression, and Veillonellaceae was associated with higher TNF-a mRNA expression and serum insulin concentration. In conclusion, our study is novel in showing that TRIM31 deficiency is associated with impaired glucose metabolism and disrupted gut microbiota in mice. This study contributes to the theoretical foundation on the potential relationship between TRIM31 deficiency and the development of abnormal glucose metabolism. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neuroinflammation, mainly mediated by microglia, is involved in the evolution of Alzheimer's disease (AD). Parthenolide (PTL) has diverse pharmacological effects such as anti-inflammatory and antioxidative stress. However, whether PTL can modulate microglia-mediated neuroinflammation to improve cognitive impairment in amyloid precursor protein/presenilin 1 (APP/PS1) mice is unclear., Methods: LPS/IFN-γ-induced BV2 and HMC3 microglia were used for in vitro experiments; the roles of PTL on anti-inflammatory, anti-oxidative, phagocytic activity, and neuroprotection were assessed by inflammatory cytokines assays, dichlorodihydrofluorescein diacetate, phagocytosis, and cell counting kit-8 assays. Western blot and immunofluorescence（IF） were used to examine related molecular mechanisms. In vivo, IF and western blot were applied in LPS-treated wild-type (WT) mice and APP/PS1 mice models. The Morris water maze test was performed to evaluate the effects of PTL on cognitive disorders., Results: In vitro, PTL dramatically suppressed proinflammatory cytokines IL-6, IL-1β, and TNF-α release and increased IL-10 levels. Moreover, PTL decreased reactive oxygen species and restored microglial phagocytic activities via the AKT/MAPK/ NF-κB signaling pathway. Importantly, we discovered that PTL obviously enhanced TRIM31 expression and siTRIM31 elevated proinflammatory cytokine levels. Furthermore, we determined that the anti-inflammatory role of PTL was mostly TRIM31/NLRP3 signaling-dependent. In vivo, PTL alleviated microgliosis and astrogliosis in LPS-treated WT and APP/PS1 mice. Additionally, PTL significantly ameliorated memory and learning deficits in cognitive behaviors., Conclusions: PTL improved cognitive and behavioral dysfunction, inhibited neuroinflammation, and showed potent anti-neuroinflammatory activity and neuroprotective effects by improving the MAPK/TRIM31/NLRP3 axis. Our study emphasized the therapeutic potential of PTL for improving cognitive disorders during AD progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

[Display omitted] • Cynapanoside A ameliorates systemic metabolic syndrome and obesity in HFD-fed mice. • Cynapanoside A attenuates podocyte injury-associated kidney injury in HFD-fed mice. • Cynapanoside A reduces lipid deposition and inflammatory response in HFD-treated mice. • Cynapanoside A improves TRIM31 signaling in kidney of HFD-fed mice. • Cynapanoside A mitigates lipid deposition in podocytes. Obesity is a major predictive factor for the diabetic nephropathy (DN). However, the precise mechanism and therapeutic approach still require to be investigated. Cynapanosides A (CPS-A) is a glycoside derived from the Chinese drug Cynanchum paniculatum that has numerous pharmacological activities, but its regulatory function on obesity-induced kidney disease is still obscure. In the present study, we attempted to explore the renoprotective effects of CPS-A on the established DN in high fat diet (HFD)-fed mice, and the underlying mechanisms. We initially found that CPS-A significantly ameliorated the obesity and metabolic syndrome in mice with HFD feeding. Mice with HFD-induced DN exerted renal dysfunctions, indicated by the elevated functional parameters, including up-regulated blood urea nitrogen (BUN), urine albumin and creatinine, which were significantly attenuated by CPS-A in obese mice. Moreover, histological changes including glomerular enlargement, sclerosis index and collagen deposition in kidney of obese mice were detected, while being strongly ameliorated by CPS-A. Additionally, podocyte loss induced by HFD was also markedly mitigated in mice with CPS-A supplementation. HFD feeding also led to lipid deposition and inflammatory response in renal tissues of obese mice, whereas being considerably attenuated after CPS-A consumption. Intriguingly, we found that tripartite motif-containing protein 31 (TRIM31) signaling might be a crucial mechanism for CPS-A to perform its renoprotective functions in mice with DN. The anti-inflammatory, anti-fibrotic and anti-dyslipidemia capacities of CPS-A were confirmed in the mouse podocytes under varying metabolic stresses, which were however almost abolished upon TRIM31 ablation. These data elucidated that TRIM31 expression was largely required for CPS-A to perform its renoprotective effects. Collectively, our study is the first to reveal that CPS-A may be a promising therapeutic strategy for the treatment of obesity-induced DN or associated kidney disease. [ABSTRACT FROM AUTHOR]

Tripartite motif (TRIM) 31 is a new member of the TRIM family and functions as an E3 ubiquitin ligase. Abnormal TRIM31 expression leads to a variety of pathological conditions, such as cancer, innate immunity diseases, sepsis-induced myocardial dysfunction, cerebral ischemic injury, nonalcoholic fatty liver disease and hypertensive nephropathy. In this review, we comprehensively overview the structure, expression and regulation of TRIM31 in cancer. Moreover, we discuss the dual role of TRIM31 in human cancer, and this dual role may be linked to its involvement in the selective regulation of several pivotal cellular signaling pathways: the p53 tumor suppressor, mTORC1, PI3K-AKT, NF-κB and Wnt/β-catenin pathways. In addition, we also discuss the emerging role of TRIM31 in innate immunity, autophagy and its growing sphere of influence across multiple human pathologies. Finally, a better understanding of the dual role of TRIM31 in cancer may provide new therapeutic strategies aimed at inhibiting the cancer-promoting effects of TRIM31 without affecting its tumor suppressor effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Lin, Hua and Wang.)

Background: Acute myeloid leukemia (AML) is one of the most common malignant myeloid diseases in adults with a dismal prognosis. We aimed to explore the effects of circNFIX on the proliferation and apoptosis of AML cells., Methods: The expressions of circNFIX, miR-876-3p and tripartite motif (TRIM) 31 in the bone marrow specimens of AML patients and AML cell lines were detected by qRT-PCR or western blot. Cell proliferation was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-ethynyl-29-deoxyuridine (EdU) assays. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was used to detect protein expression. The relationship between miR-876-3p and circNFIX or TRIM31 was identified by dual-luciferase reporter assay or RNA pull-down assay., Results: The expression level of circNFIX was significantly increased in the bone marrow samples of AML patients and AML cells when compared with normal controls. CircNFIX silencing inhibited AML cell proliferation and promoted apoptosis. Inhibition of miR-876-3p reversed the effect of circNFIX knockdown on AML cell progression. In addition, circNFIX indirectly regulated TRIM31 through miR-876-3p. Further, TRIM31 overexpression counteracted the effect of circNFIX silencing on AML cell proliferation and apoptosis., Conclusion: CircNFIX knockdown could suppress the proliferation and induce the apoptosis of AML cells by targeting the miR-876-3p/TRIM31 axis.

The present study aims to investigate expression pattern and biological roles of TRIM31 in human non-small cell lung cancer (NSCLC). We examined TRIM31 expression in 116 NSCLC tissues and 20 corresponding normal lung tissues by immumohistochemistry. We found TRIM31 downregulation in 47 out of 116 (40.5 %) cancer samples, which correlated with tumor status ( p = 0.0132), advanced p-TNM stage ( p = 0.001), and nodal metastasis ( p = 0.0382). TRIM31 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TRIM31 plasmid was performed in H157 and H1299 cells. TRIM31 overexpression inhibited cell growth rate and colony formation ability in both cell lines. In addition, expression of cell cycle regulator cyclin D1 and cyclin E were decreased after TRIM31 transfection. In conclusion, TRIM31 might serve as a tumor suppressor in non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

The intestine-specific transcription factor Cdx2 is essential for intestinal homeostasis and has been implicated in the pathogenesis of disorders including inflammatory bowel disease. However, the mechanism by which Cdx2 influences intestinal disease is not clear. Here, we present evidence supporting a novel Cdx2-TRIM31-NLRP3 (NLR family, pyrin domain containing 3) signaling pathway, which may represent a mechanistic means by which Cdx2 impacts intestinal inflammation. We found that conditional loss of Cdx function resulted in an increase in proinflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, in the mouse colon. We further show that TRIM31, which encodes a suppressor of NLRP3 (a central component of the NLRP3 inflammasome complex) is a novel Cdx2 target gene and is attenuated in the colon of Cdx conditional mutants. Consistent with this, we found that attenuation of TRIM31 in Cdx mutant intestine occurs concomitant with elevated levels of NLRP3 and an increase in inflammasome products. We demonstrate that specific inhibition of NLRP3 activity significantly reduced IL-1β and IL-6 levels and extended the life span of Cdx conditional mutants, reflecting the therapeutic potential of targeting NLRP3. Tumor necrosis factor-alpha levels were also induced independent of NLRP3, potentially via elevated activity of the proinflammatory NF-κB signaling pathway in Cdx mutants. Finally, in silico analysis of ulcerative colitis patients revealed attenuation of CDX2 and TRIM31 expression coincident with enhanced expression of proinflammatory cytokines. We conclude that the novel Cdx2-TRIM31-NLRP3 signaling pathway promotes proinflammatory cytokine expression, and its inhibition may have therapeutic potential in human intestinal diseases., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Tripartite motif-containing protein (TRIM) family proteins are involved in a broad range of biological processes and, consistently, their alterations result in diverse pathological conditions such as genetic diseases, viral infection and cancer development. In this study, we found that one of the TRIM family proteins, TRIM31, is highly expressed in the gastrointestinal tract and interacts with p52Shc, one of the signal transducers. We also found by a binding assay that almost the whole region other than the RING domain is required for the binding to p52Shc but found by pulse-chase analysis that overexpression of TRIM31 does not affect the stability of p52Shc. Moreover, we found that overexpression of TRIM31 suppresses anchorage-independent cell growth induced by the active form of c-Src. These results suggest that TRIM31 attenuates c-Src signaling via p52Shc under anchorage-independent growth conditions and is potentially associated with growth activity of cells in the gastrointestinal tract. [Copyright &y& Elsevier]

• TRIM31 is mutated in an HBV patient. • TRIM31 promotes HBx K95 site ubiquitination. • TRIM31 is a type III interferon stimulated gene. TRIM5γ, together with TRIM31, has been shown to promote HBx ubiquitination and degradation. This study aimed to explore whether a patient with HCC (hepatic cell carcinoma) having a small nucleotide inserted into the TRIM31 gene, which made a shorter transcript stop at 768 bp, would result in blocking the activity of TRIM31 in promoting HBx degradation. Besides, this study aimed to determine the binding region of the TRIM31–TRIM5γ–HBx complex. HBV (Hepatitis B virus) infection was reported to induce type-III IFN but not type-I or type-II IFNs, here TRIM31 was found to be a type III rather than a type I stimulated gene, which was indispensable in inhibiting the hepatitis B virus replication by the interferon families. Thus, this study further identified the critical role of TRIM31 in the host–hepatitis B virus interaction. [Display omitted] [ABSTRACT FROM AUTHOR]

Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense. [Display omitted] • Arginine monomethylation at MAVS R52 inhibits its interaction with RIG-I • PRMT7 negatively regulates immune responses by catalyzing MAVS monomethylation • Virus-induced automethylation of PRMT7 at R32 inhibits its aggregation • MAVS recruits SMURF1 to degrade PRMT7 upon RNA virus infection Zhu et al. demonstrate that PRMT7 forms aggregates to catalyze MAVS monomethylation at arginine residue 52, which tightly blocks RLR signaling. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32, and MAVS recruits SMURF1 to degrade PRMT7, which ensure the timely activation of antiviral defense. [ABSTRACT FROM AUTHOR]

Tripartite motif (TRIM) 31 has been implicated in diverse biological and pathological conditions. However, whether TRIM31 plays a role in ischemic stroke progression is not clarified. Here we demonstrated that TRIM31 was significantly downregulated in the ischemic brain and the deficiency of TRIM31 alleviated brain injury induced by middle cerebral artery occlusion by reducing reactive oxygen species production and maintaining mitochondrial homeostasis. Mechanistically, we found that TRIM31 is an E3 ubiquitin ligase for TP53-induced glycolysis and apoptosis regulator (TIGAR), which confers protection against brain ischemia by increasing the pentose phosphate pathway flux and preserving mitochondria function. TRIM31 interacted with TIGAR and promoted the polyubiquitination of TIGAR, consequently facilitated its degradation in a proteasome-dependent pathway. Furthermore, TIGAR knockdown effectively abolished the protective effect of TRIM31 deficiency after cerebral ischemia. In conclusion, we identified that TRIM31 was a novel E3 ubiquitin ligase for TIGAR, played a critical role in regulating its protein level, and subsequently involved in the ischemic brain injury, suggesting TRIM31 as a potential therapeutic target for ischemic stroke., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sepsis is a major condition caused by an overwhelming inflammatory response to an infection. Sepsis-induced myocardial dysfunction (SIMD) is a common complication in septic patients and a major predictor of morbidity and mortality. Here, we investigated the role of tripartite motif 31 (TRIM31) protein in sepsis progression in vitro and in vivo . Quantitative real-time PCR and western blot were used to detect the expression levels of relative genes and proteins. Cell proliferation and apoptosis were evaluated to determine cell viability. H&E and IHC staining were performed to examine morphological and pathological changes in mice. ELISA assay was used to detect inflammatory factors. TRIM31 was upregulated in septic patients compared with normal people. TRIM31 depletion reduced LPS-induced apoptosis whereas TRIM31 overexpression-elevated LPS-induced apoptosis. Furthermore, TRIM31 interacted with and ubiquitinated transforming growth factor-β-activated kinase-1 (TAK1), resulting in TAK1 activation and subsequent induction of NF-κB signaling. Of note, Trim31 depletion or blockade by PDTC treatment inhibited LPS-induced apoptosis in vivo . In conclusion, TRIM31 played an important role in SIMD by activating TAK1-mediated NF-κB signaling pathway.

Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment., (© 2020 The Author(s).)

Aberrant expression of microRNAs (miRNAs) has been widely reported in many malignant tumors, and dysregulated miRNAs play an important role in the malignant progression of tumors. It has been reported that miR‑29c‑3p expression is dysregulated in tumors and promotes the development of tumors, especially in hepatocellular carcinoma (HCC). However, the specific mechanism of miR‑29c‑3p in HCC is not clear. The present study demonstrated that miR‑29c‑3p was expressed at low levels in HCC patients and cell lines and that its decreased expression was closely related to poor prognosis of HCC patients. Overexpression of miR‑29c‑3p could significantly inhibit the proliferation and migration of HCC cells in vitro and suppress the HCC tumor growth in vivo. The luciferase reporter assay demonstrated that miR‑29c‑3p directly bound to tripartite motif containing 31 (TRIM31) and suppressed TRIM31 expression. Finally, upregulation of TRIM31 could partially abolish the tumor suppressing roles of miR‑29c‑3p in HCC. Overall, miR‑29c‑3p, as a tumor suppressor gene, was revealed to inhibit the malignant progression of HCC by reducing the expression of TRIM31 and may be used as a potential therapeutic target for the precise treatment of HCC.

Background: Drug resistance is well known as a major obstacle for cancer recurrence and treatment failure, leading to poor survival in pancreatic cancer, which is a highly aggressive tumor. Identifying effective strategies to overcome drug resistance would have a significant clinical impact for patients with pancreatic cancer. Methods: The protein and mRNA expression of TRIM31 in pancreatic cancer cell lines and patient tissues were determined using Real-time PCR and Western blot, respectively. 89 human pancreatic cancer tissue samples were analyzed by IHC to investigate the association between TRIM31 expression and the clinicopathological characteristics of pancreatic cancer patients. Functional assays, such as MTT, FACS, and Tunel assay used to determine the oncogenic role of TRIM31 in human pancreatic cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of TRIM31 promotes chemoresistance in pancreatic cancer cells. Results: The expression of TRIM31was markedly upregulated in pancreatic cancer cell lines and tissues, and high TRIM31 expression was associated with an aggressive phenotype and poor prognosis with pancreatic cancer patients. TRIM31 overexpression confers gemcitabine resistance on pancreatic cancer cells; however, inhibition of TRIM31 sensitized pancreatic cancer cell lines to gemcitabine cytotoxicity both in vitro and in vivo . Additionally, TRIM31 upregulated the levels of nuclear p65 by promoting K63-linked polyubiquitination of tumor necrosis factor receptor-associated factor 2 (TRAF2) and sustained the activation of nuclear transcription factor kappa B (NF-κB) in pancreatic cancer cells. Conclusions: Our findings provided evidence that TRIM31 is a potential therapeutic target for patients with pancreatic cancer. Targeting TRIM31 signaling may be a promising strategy to enhance gemcitabine response during pancreatic cancer chemo-resistance., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.