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The activation of key signaling pathways downstream of antigen receptor engagement is critically required for normal lymphocyte activation during the adaptive immune response. CARD11 is a multidomain signaling scaffold protein required for antigen receptor signaling to NF-κB, c-Jun N-terminal kinase, and mTOR. Germline mutations in the CARD11 gene result in at least four types of primary immunodeficiency, and somatic CARD11 gain-of-function mutations drive constitutive NF-κB activity in diffuse large B cell lymphoma and other lymphoid cancers. In response to antigen receptor triggering, CARD11 transitions from a closed, inactive state to an open, active scaffold that recruits multiple signaling partners into a complex to relay downstream signaling. However, how this signal-induced CARD11 conversion occurs remains poorly understood. Here we investigate the role of Inducible Element 1 (IE1), a short regulatory element in the CARD11 Inhibitory Domain, in the CARD11 signaling cycle. We find that IE1 controls the signal-dependent Opening Step that makes CARD11 accessible to the binding of cofactors, including Bcl10, MALT1, and the HOIP catalytic subunit of the linear ubiquitin chain assembly complex. Surprisingly, we find that IE1 is also required at an independent step for the maximal activation of HOIP and MALT1 enzymatic activity after cofactor recruitment to CARD11. This role of IE1 reveals that there is an Enzymatic Activation Step in the CARD11 signaling cycle that is distinct from the Cofactor Association Step. Our results indicate that CARD11 has evolved to actively coordinate scaffold opening and the induction of enzymatic activity among recruited cofactors during antigen receptor signaling.

In this paper, a generalized Ablowitz–Ladik system is systemically investigated via the Darboux transformation method. Soliton solutions and conservation laws are presented. Depending on the choices of parameters, the dynamic behaviors are discussed graphically.

Single-nucleotide polymorphisms (SNPs) identified by Genome-Wide Association Studies (GWASs) have been determined to closely connect with multiple diseases. Previous studies revealed one underlying mechanism that SNPs located within the regulatory elements could affect the encoding gene expression through long-range regulation. SNP rs6854845 was suggested to be a risk of colon cancer in human population. Nevertheless, the underlying molecular mechanism for colon carcinogenesis remains largely unknown. In present study, rs6854845 with G > T mutation in situ in FHC, HCT-116 and SW-480 cells were generated by Crispr/Cas9. The nearby chromatin organization was investigated by chromatin conformation capture (3C). And the expression of coding gene regulated by super-enhancer (SE) was detected by real-time PCR. We observed a significantly different pattern of the genome organization upon rs6854845 generation in colon epithelial cells but not in colon cancer cells. Moreover, we observed the shifted enrichment of H3K4me1 and H3K27ac at the SE (chr4:75.7M-76.0 M) where rs6854845 located. Furthermore, we observed that the transcription of the gene clusters regulated by SE were affected by rs6854845 in colon cells. Overall, our results demonstrated that SNP rs6854845 located in SE could destroy the long-range chromosomal interaction between SE and target gene clusters thereby affecting the transcription of these genes.

Retinoic acid‐inducible gene I (RIG‐I) and melanoma differentiation‐associated gene 5 (MDA5) are cytoplasmic sensors crucial for recognizing different species of viral RNAs, which triggers the production of type I interferons (IFNs) and inflammatory cytokines. Here, we identify RING finger protein 123 (RNF123) as a negative regulator of RIG‐I and MDA5. Overexpression of RNF123 inhibits IFN‐β production triggered by Sendai virus (SeV) and encephalomyocarditis picornavirus (EMCV). Knockdown or knockout of endogenous RNF123 potentiates IFN‐β production triggered by SeV and EMCV, but not by the sensor of DNA viruses cGAS. RNF123 associates with RIG‐I and MDA5 in both endogenous and exogenous cases in a viral infection‐inducible manner. The SPRY and coiled‐coil, but not the RING, domains of RNF123 are required for the inhibitory function. RNF123 interacts with the N‐terminal CARD domains of RIG‐I/MDA5 and competes with the downstream adaptor VISA/MAVS/IPS‐1/Cardif for RIG‐I/MDA5 CARD binding. These findings suggest that RNF123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG‐I and MDA5, a function that does not depend on its E3 ligase activity.

CARD11 functions as a key signaling scaffold that controls antigen-induced lymphocyte activation during the adaptive immune response. Somatic mutations in CARD11 are frequently found in Non-Hodgkin lymphoma, and at least three classes of germline CARD11 mutations have been described as the basis for primary immunodeficiency. In this review, we summarize our current understanding of how CARD11 signals, how its activity is regulated, and how mutations bypass normal regulation to cause disease.

Colorectal cancer (CRC) metastases accounts for two thirds of death cases. Recently, genetic instability has been recognized as one of the hallmarks of metastatic microenvironment. In this study, we identified the relationship between Rad51, a key factor to perform DNA homologous recombination repair, and CRC metastasis, and further at the first time explored the effect of O-GlcNAc glycosylation of Rad51 protein on CRC cells invasion. Generally, the study indicates a novel posttranslational modification of Rad51 protein may play an important regulatory role in the process of CRC cells invasion and represent a potential therapeutic target for clinical management of CRC patients.

The activation of NF-κB downstream of T cell receptor (TCR) engagement is a key signaling step required for normal lymphocyte function during the adaptive immune response. During TCR signaling, the adaptor protein Bcl10 is inducibly recruited to the CARD11 scaffold protein as part of a multicomponent complex that induces IκB kinase (IKK) activity and NF-κB activation. Here, we show that a consequence of this recruitment is the TCR-induced conjugation of Bcl10 with linear-linked polyubiquitin chains to generate the signaling intermediate Lin(Ub)n-Bcl10, which is required for the association of Bcl10 with the NEMO subunit of the IKK complex. The TCR-induced generation of Lin(Ub)n-Bcl10 requires Bcl10 lysines 17, 31, and 63, CARD11, MALT1, and the HOIP subunit of the linear ubiquitin chain assembly complex (LUBAC) but not the HOIP accessory protein SHARPIN. CARD11 promotes signal-induced Lin(Ub)n-Bcl10 generation by co-recruiting Bcl10 with HOIP, thereby bringing substrate to enzyme. The CARD11-HOIP interaction is rendered TCR-inducible by the four autoinhibitory repressive elements in the CARD11 inhibitory domain and involves the CARD11 coiled-coil domain and two independent regions of HOIP. Interestingly, oncogenic CARD11 variants associated with diffuse large B cell lymphoma spontaneously induce Lin(Ub)n-Bcl10 production to extents that correlate with their abilities to activate NF-κB and with their enhanced abilities to bind HOIP and Bcl10. Our results define molecular determinants that control the production of Lin(Ub)n-Bcl10, an important signaling intermediate in TCR and oncogenic CARD11 signaling.

Retinoic acid-inducible gene I (RIG-I) is a key sensor for recognizing nucleic acids derived from RNA viruses and triggers beta interferon (IFN-β) production. Because of its important role in antiviral innate immunity, the activity of RIG-I must be tightly controlled. Here, we used yeast two-hybrid screening to identify a SEC14 family member, SEC14L1, as a RIG-I-associated negative regulator. Transfected SEC14L1 interacted with RIG-I, and endogenous SEC14L1 associated with RIG-I in a viral infection-inducible manner. Overexpression of SEC14L1 inhibited transcriptional activity of the IFN-β promoter induced by RIG-I but not TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Knockdown of endogenous SEC14L1 in both HEK293T cells and HT1080 cells potentiated RIG-I and Sendai virus-triggered IFN-β production as well as attenuated the replication of Newcastle disease virus. SEC14L1 interacted with the N-terminal domain of RIG-I (RIG-I caspase activation and recruitment domain [RIG-I-CARD]) and competed with VISA/MAVS/IPS-1/Cardif for RIG-I-CARD binding. Domain mapping further indicated that the PRELI-MSF1 and CRAL-TRIO domains but not the GOLD domain of SEC14L1 are required for interaction and inhibitory function. These findings suggest that SEC14L1 functions as a novel negative regulator of RIG-I-mediated antiviral signaling by preventing RIG-I interaction with the downstream effector.

Recent reports suggest that src suppressed c kinase substrates (SSeCKS) are early inflammatory response protein. However, there is only scarce knowledge on the functional role of SSeCKS in liver under conditions of acute inflammation. In the present study, we investigated SSeCKS expression in liver after administration of carbon tetrachloride (CCl4) in rats and in isolated primary hepatic stellate cells (HSCs) upon activation on a plastic dish. We found that SSeCKS mRNA was hardly detectable in healthy liver tissue and further increased in carbon tetrachloride-mediated acute liver failure. SSeCKS protein expression was mainly found in hepatic stellate cells. In vitro, SSeCKS expression in activated rat HSCs was dramatically increased. The upregulation of SSeCKS protein expression in rat HSCs during activation in vitro and in vivo suggested the possibility of SSeCKS, an important part of function of the activated HSCs, perhaps through modulation of liver regeneration or formation of liver fibrosis after various injuries.

Yangpu Port has inhomogeneous soft soil with the properties of high water content, high void ratio, high compressibility and low shear strength. Based on soft soil ground treatment engineering practice, the geological characteristics are summarized, the ground treatment methods are comparatively analyzed, static-dynamic drainage consolidation method is chosen to treat the soft soil ground, the reinforcing mechanism of vertical and horizontal drainage system are discussed, the design of drainage system, preloading and dynamic consolidation are researched and the surface settlement monitoring, pore water pressure monitoring, side piling displacement monitoring, laboratory soil test and plate loading tests are carried out. The results show that average surface settlement is 1170.8 mm, the physical and mechanical properties of soft soil are improved and the characteristic value of foundation bearing capacity is greater than 120kPa.

Based on deformation of adjacent building with shallow foundation of foundation pit excavation, Midas GTS is adopted to establish the finite element model. Through the numerical simulation, the maximum horizontal and vertical displacement in different conditions, Influence of different SMW pile stiffness and influence of different anchor position are analyzed. The results show that (1) horizontal deformation of SMW pile is decreased at the anchor construction; (2) compared with maximum horizontal displacement of SMW pile with 25a25b28a, the maximum horizontal displacement of SMW pile with 28b is increased by 50.9, 43.3, 11.5% respectively; (3) compared with the second anchor at 1.5, 3.5m, the horizontal displacement of adjacent building is minimal by the second anchor at 2.5m.

Host cells orchestrate the production of IFN-β upon detecting invading viral pathogens. Here, we report that Ring finger protein 166 (RNF166) potentiates RNA virus-triggered IFN-β production. Overexpression of RNF166 rather than its homologous proteins RNF114, RNF125 and RNF138, enhanced Sendai virus (SeV)-induced activation of the IFN-β promoter. Knockdown of endogenous RNF166, but not other RNFs, inhibited the IFN-β production induced by SeV and encephalomyocarditis virus. RNF166 interacted with TRAF3 and TRAF6. SeV-induced ubiquitination of TRAF3 and TRAF6 was suppressed when endogenous RNF166 rather than RNF114/138 was knocked down. These findings suggest that RNF166 positively regulates RNA virus-triggered IFN-β production by enhancing the ubiquitination of TRAF3 and TRAF6.

Based on the appearance of crack of enclosure piles on a foundation pit, Midas GTS is adopted to establish the finite element model. Through the numerical simulation, the influence of the direction of wind load, wind scale and prestress of anchor are analyzed, the worst wind load direction, unfavorable construction condition, maximum moment of enclosure piles are ensured, crack width in different disadvantageous factors are calculated, which provides a guide for continuous construction.

Retinoic acid-inducible gene I (RIG-I) recognizes RNA virus-derived nucleic acids, which leads to the production of type I interferon (IFN) in most cell types. Tight regulation of RIG-I activity is important to prevent ultra-immune responses. In this study, we identified an ARF-like (ARL) family member, ARL16, as a protein that interacts with RIG-I. Overexpression of ARL16, but not its homologous proteins ARL1 and ARF1, inhibited RIG-I-mediated downstream signaling and antiviral activity. Knockdown of endogenous ARL16 by RNAi potentiated Sendai virus-induced IFN-β expression and vesicular stomatitis virus replication. ARL16 interacted with the C-terminal domain (CTD) of RIG-I to suppress the association between RIG-I and RNA. ARL16 (T37N) and ARL16Δ45–54, which were restricted to the GTP-disassociated form, did not interact with RIG-I and also lost the inhibitory function. Furthermore, we suggest that endogenous ARL16 changes to GTP binding status upon viral infection and binds with the RIG-I CTD to negatively control its signaling activity. These findings suggested a novel innate immune function for an ARL family member, and a GTP-dependent model in which RIG-I is regulated.

Toll-like receptors (TLRs) act as sensors of microbial components and elicit innate immune responses. All TLR signaling pathways activate the nuclear factor-kappaB (NF-kappaB), which controls the expression of inflammatory cytokine genes. Transforming growth factor-beta-activated kinase 1 (TAK1) is a serine/threonine protein kinase that is critically involved in the activation of NF-kappaB by tumor necrosis factor (TNFalpha), interleukin-1beta (IL-1beta) and TLR ligands. In this study, we identified a novel protein, WD40 domain repeat protein 34 (WDR34) as a TAK1-interacting protein in yeast two-hybrid screens. WDR34 interacted with TAK1, TAK1-binding protein 2 (TAB2), TAK1-binding protein 3 (TAB3) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in overexpression and under physiological conditions. Overexpression of WDR34 inhibited IL-1beta-, polyI:C- and lipopolysaccharide (LPS)-induced but not TNFalpha-induced NF-kappaB activation, whereas knockdown of WDR34 by a RNA-interference construct potentiated NF-kappaB activation by these ligands. Our findings suggest that WDR34 is a TAK1-associated inhibitor of the IL-1R/TLR3/TLR4-induced NF-kappaB activation pathway.

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway appears to be a key regulator in cervical carcinogenesis. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is principally involved in the homeostatic maintenance of PI3K/Akt signaling and PTEN has been identified to play an important role in the occurrence and development of cervical cancer. MicroRNA (miRNA)-494 has been proven to be involved in the carcinogenesis and development of various types of cancer by directly targeting PTEN. However the role, mechanism and clinical significance of miR-494 in cervical cancer have not been further reported. In the present study, we analyzed the expression of miR-494 in -with PTEN expression and clinicopathological data of cervical cancer patients. The results showed that miR-494 expression was significantly upregulated in human cervical cancer cell lines and tissues. miR-494 upregulation was significantly associated with PTEN downregulation, adverse clinicopathological characteristics, poor overall and progression-free survival and poor prognosis. In vitro experiments showed that inhibition of miR-494 suppressed cell proliferation and growth by directly targeting the 3'-untranslated region (3'-UTR) of PTEN mRNA. These findings identified a novel molecular mechanism involved in the regulation of PTEN expression and cervical cancer progression. Results of the present study indicated that miR-494 may have an essential role in the carcinogenesis and progression of cervical cancer and targeting miR-494 may be a promising therapeutic strategy for the treatment of cervical cancer.

RIG-I and MDA5 are cytoplasmic sensors that recognize different species of viral RNAs, leads to activation of the transcription factors IRF3 and NF-kappaB, which collaborate to induce type I interferons. In this study, we identified REUL, a RING-finger protein, as a specific RIG-I-interacting protein. REUL was associated with RIG-I, but not MDA5, through its PRY and SPRY domains. Overexpression of REUL potently potentiated RIG-I-, but not MDA5-mediated downstream signalling and antiviral activity. In contrast, the RING domain deletion mutant of REUL suppressed Sendai virus (SV)-induced, but not cytoplasmic polyI:C-induced activation of IFN-beta promoter. Knockdown of endogenous REUL by RNAi inhibited SV-triggered IFN-beta expression, and also increased VSV replication. Full-length RIG-I, but not the CARD domain deletion mutant of RIG-I, underwent ubiquitination induced by REUL. The Lys 154, 164, and 172 residues of the RIG-I CARD domain were critical for efficient REUL-mediated ubiquitination, as well as the ability of RIG-I to induce activation of IFN-beta promoter. These findings suggest that REUL is an E3 ubiquitin ligase of RIG-I and specifically stimulates RIG-I-mediated innate antiviral activity.