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Migraine is a complex disabling condition which is associated with dysregulation of several pathways particularly those being associated with immune responses. In order to assess contribution of protein inhibitor of activated STAT (PIAS) in the pathogenesis of migraine, we quantified expression levels of PIAS1-PIAS4 genes in the circulation of patients with migraine compared with controls. Expression of PIAS1 was substantially lower in total migraineurs compared with controls (ratio of mean expressions (RME) = 0.18, SE = 0.29, P value < 0.001) and in both male and female migraineurs compared with sex-matched controls. Expression of PIAS2 was lower in migraineurs without aura compared with controls (RME = 0.64, SE = 0.31, P value = 0.04) and in male subgroup of these patients compared with male controls (RME = 0.60, SE = 0.22, P value < 0.001). In migraineurs with aura, downregulation of PIAS2 was only observed among male subgroups (RME = 0.37, SE = 0.49, P value = 0.01). PIAS3 was downregulated in total male migraineurs (RME = 0.52, SE = 0.43, P value = 0.04) and in male migraineurs with aura (RME = 0.49, SE = 0.45, P value = 0.03) compared with male controls. Finally, PIAS4 was upregulated in total migraineurs (RME = 3.78, SE = 0. 34, P value < 0.001), female migraineurs (RME = 5.26, SE = 0.36, P value < 0.001), migraineurs with aura (RME = 4.24, SE = 0.42, P value < 0.001), female migraineurs with aura (RME = 6.13, SE = 0.47, P value < 0.001), migraineurs without aura (RME = 3.33, SE = 0.38, P value < 0.001), and female migraineurs without aura (RME = 4.47, SE = 0.41, P value < 0.001) compared with the corresponding controls. The present study suggests contribution of PIAS genes in the pathogenesis of migraine and warrants future studies to clarify the functional routes of their contribution., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Protein inhibitors of activated STAT (PIAS) are involved in the regulation of the JAK/STAT signaling pathway and have interactions with NF-κB, p73 and p53. These proteins regulate immune responses; therefore dysregulation in their expression leads to several immune-mediated disorders. In the present study, we examined expression of PIAS1 - 4 in peripheral blood of patients with acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIDP) compared with healthy subjects. We demonstrated down-regulation of all PIAS genes in both AIDP and CIDP cases compared with controls. Similarly, comparisons in gender-based groups revealed down-regulation of these gene0s in patients of each gender compared with gender-matched controls. There was no significant difference in expression of PIAS genes between AIDP and CIDP cases. Based on the area under the receiver operating characteristic curves, PIAS1 - 4 genes could distinguish between inflammatory demyelinating polyradiculoneuropathy and healthy status with accuracy values of 0.87, 0.87, 0.79 and 0.80, respectively. In differentiation between AIDP cases and healthy controls, these values were 0.92, 0.92, 0.83 and 0.86, respectively. Finally, PIAS1 - 4 genes could discriminate CIDP from healthy status with accuracy values of 0.82, 0.83, 0.75 and 0.75, respectively. The current study underscores the role of PIAS genes in the pathogenesis of inflammatory demyelinating polyradiculoneuropathy and their potential usage as biomarkers., 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 © 2021 Ghafouri-Fard, Hussen, Nicknafs, Nazer, Sayad and Taheri.)

Nur77 (NGFI-B) is a nuclear receptor that belongs to the Nr4a family of orphan nuclear receptors (Nr4a1). This transcription factor has been implicated in the regulation of multiple functions, such as cell cycle regulation, apoptosis, inflammation, glucose and lipid metabolism, and brain function. However, the mechanisms involved in its different regulatory properties remain unclear. In search for regulatory mechanisms of Nur77 function, we identified that Protein Inhibitor of Activated STAT gamma (PIASγ), an E3 SUMO-protein ligase, potently repressed Nur77 transcriptional activity in HEK-293T cells. This PIASγ activity was sensitive to Sentrin SUMO-specific protease 1 (SENP1). Substitution of two putative phylogenetically well-conserved small ubiquitin-like modifier (SUMO) acceptor sites, lysine 102 (K102) and 577 (K577) by arginine residues (R) modulated Nur77 transcriptional activity. In particular, Nur77-K102R and Nur77-K102R/K577R mutants strongly decreased the transcriptional activity of Nur77, whereas single K577R substitution increased transcriptional activity of Nur77. Repression of Nur77 transcriptional activity by SUMO2 and PIASγ was reduced by the K577R mutation, whereas the K102R mutant remained insensitive to SUMO2. Interestingly, the roles of these SUMO acceptor sites in Nur77 are distinct from previously observed activities on its close homolog Nurr1. Thus, the present study identified SUMO2 and PIASγ as important transcriptional co-regulators of Nur77., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Protein inhibitor of activated STAT (PIAS) plays a critical role in the feedback modulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway as a negative regulator in mammals and Drosophila, but the function of PIAS in crustaceans is still unclear. In this study, a PIAS termed LvPIAS was cloned and characterized from Litopenaeus vannamei. The full length of LvPIAS was 3065 bp, including a 2361 bp open reading frame (ORF) coding for a protein of 786 aa. LvPIAS expression was most abundant in muscle and could respond to the challenge of LPS, Vibrio parahaemolyticus, Staphhylococcus aureus, Poly I: C and white spot syndrome virus (WSSV). LvPIAS could be induced by the transcription factor LvSTAT, but LvPIAS could inhibit the transcriptional activity of LvSTAT to the LvPIAS promoter conversely, which indicated that there was a negative feedback loop between LvSTAT and LvPIAS. Furthermore, RNAi-mediated knockdown of LvPIAS shrimps showed higher survival rate to WSSV infection than those in the control group (dsGFP injection), suggesting that LvPIAS may play a negatively role against WSSV infection., (Copyright © 2019. Published by Elsevier Ltd.)

Aim: Protein inhibitor of activated STAT ( PIAS ) family includes transcriptional regulator proteins with SUMO E3 ligase activity. They regulate expression of several genes involved in cell proliferation, differentiation and survival. Method: We evaluated expression of PIAS1-4 genes in 54 breast cancer tissues and their paired adjacent noncancerous tissues. Results: PIAS2 and PIAS3 genes were significantly downregulated in tumoral tissues compared with adjacent noncancerous tissues. PIAS1-3 expressions were significantly lower in estrogen receptor (ER+) samples compared with ER- samples while PIAS4 had the opposite trend. PIAS3 expression was significantly higher in grade 1 samples compared with grade 2 samples. Conclusion: These findings highlight the role of PIAS genes in the pathogenesis of breast cancer and their association with determinants of response to antihormone therapies.

Protein inhibitor of activated STAT (PIAS) proteins are activation-suppressing proteins for signal transducer and activator of transcription (STAT), which involves gene transcriptional regulation. The inhibitory mechanism of PIAS proteins in the Janus kinase (JAK)/STAT signaling pathway has been well studied in mammals and Drosophila . However, the roles of PIAS in crustaceans are unclear. In the present study, we identified PIAS in kuruma shrimp Marsupenaeus japonicus and found that its relative expression could be induced by Vibrio anguillarum stimulation. To explore the function of PIAS in shrimp infected with V. anguillarum , we performed an RNA interference assay. After knockdown of PIAS expression in shrimp subjected to V. anguillarum infection, bacterial clearance was enhanced and the survival rate increased compared with those in the control shrimp ( dsGFP injection). Simultaneously, the expression levels of antimicrobial peptides (AMPs), including anti-lipopolysaccharide factor (ALF) A1, C1, C2, and CruI-1, increased. Further study revealed that knockdown of PIAS also enhanced STAT phosphorylation and translocation. Pulldown assay indicated that PIAS interacts with activated STAT in shrimp. In conclusion, PIAS negatively regulates JAK/STAT signaling by inhibiting the phosphorylation and translocation of STAT through the interaction between PIAS and STAT, which leads to the reduction of AMP expression in shrimp. Our results revealed a new mechanism of PIAS-mediated gene regulation of the STAT signal pathway.

The human telomeric protein TRF2 protects chromosome ends by facilitating their organization into the protective capping structure. Here we show that the stability of TRF2 is regulated via modification by the small ubiquitin-like modifiers (SUMO). TRF2 specifically interacts with and is sumoylated by PIAS1 in mammalian cells. The proteasome inhibitor stabilizes SUMO-conjugated TRF2 without affecting the level of unmodified TRF2, suggesting that SUMO conjugation is required for proteasomal degradation of TRF2. We also show that RNF4, a mammalian SUMO-targeted ubiquitin ligase, interacts with TRF2 in a SUMO-dependent manner and preferentially targets SUMO-conjugated TRF2 for ubiquitination. Collectively, our data demonstrate that the PIAS1-mediated sumoylation status of TRF2 serves as a molecular switch that controls the level of TRF2 at telomeres., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

NF-κB is an important regulator of immunity and inflammation, and its activation pathway has been studied extensively. The mechanisms that downregulate the activity of NF-κB have also received a lot of attention, particularly since its activity needs to be terminated to prevent chronic inflammation and subsequent tissue damage. The COMMD family has been identified as a new group of proteins involved in NF-κB termination. All ten COMMD members share the structurally conserved carboxy-terminal motif, the COMM domain, and are ubiquitously expressed. They seem to play distinct and non-redundant roles in various physiological processes, including NF-κB signaling. In this review, we describe the mechanisms and proteins involved in the termination of canonical NF-κB signaling, with a specific focus on the role of the COMMD family in the down-modulation of NF-κB., (© 2013.)