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  • TRAF and TRAF were initially

    2021-07-29

    TRAF1 and TRAF2 were initially identified as tumor necrosis factor receptor 2 (TNRF2)-associated components, TRAF4 was overexpressed in breast carcinoma cells, whereas TRAF3, TRAF5 and TRAF6 were discovered by their interaction with specific domains in the cytoplasmic tails of trans-membrane receptor CD40 [63]. TRAFs serve as essential adaptors for members of TNFR signaling pathway such as TNFR2 and CD40, and are involved in assembly of signaling complexes associated with intracellular domains of trans-membrane receptors. TRAF3 is primarily involved in thymic T cell development and B cell signaling. It also negatively regulates IL-2 that is required for conversion of precursor T cells to mature CD25+Foxp3+ regulatory T cells, a major subset of immunosuppressive CD4+ T cells that maintain peripheral immune system and prevent autoimmune diseases [64]. TRAF3 regulates Treg effector functions and humoral immune response, and accordingly TRAF3-deficiency leads to increased number of Tregs in thymus and peripheral tissues [65]. TRAF6 is an important mediator of interleukin-1 receptor (IL-1R)-associated activation of NF-κB signaling pathway and is essential for induction of immune response and maintenance of immune tolerance. TRAF6 also regulates development and functioning of B cells, T cells and macrophages. For example, in T cells TRAF6 is involved in TCR-mediated T cell activation, Th/Treg cells differentiation, CD8+ T-cell homeostasis and memory development [66]. Whereas, in Forsythoside A synthesis it promotes signal transduction via B-cell surface antigen CD40, a.k.a. tumor necrosis factor receptor superfamily member 5 (TNFRSF5), and activates extracellular signal–regulated kinases (ERKs) resulting in induction of immunoglobulin secretion. In this respect, TRAF6-deficiency in B cells results in lower number of mature B cells in spleen and bone marrow [67]. Moreover, B cell-specific TRAF6-deficient mice were demonstrated to have impaired T cell-dependent and T cell-independent humoral immune response.
    TRIM family Tripartite motif (TRIM) family of proteins are key players in regulation of intracellular signaling, cell development and innate immunity. Chromosomal location of TRIM genes suggests their importance for immune response, primarily against viral infections. Human TRIM genes are transciptionally upregulated in immune cells in response to viral pathogen-mediated induction of interferons [68], and also participate at various levels of NF-κB signaling pathway implicating regulatory functions in immunity and inflammation [69]. Previous genome-wide association analysis revealed that single nucleotide polymorphisms (SNPs) in several TRIM genes (TRIM10, TRIM15, TRIM26, TRIM39 and TRIM40) define susceptibility to MS, a chronic autoimmune disease linked to inflammatory demyelination of the central nervous system [70]. Currently there are over 70 members of TRIM family classified into 11 subgroups according to their domain architecture, as extensively reviewed in recent study [71]. TRIMs are characterized by common N-terminal tripartite RBCC motif that consists of one or two BBox domains, coiled-coil (CC) domain, and RING-finger domain that confers E3 ligase activity. The variable substrate-specific C-terminal motif includes PHD, BROMO, SPRY, COS and several others that mediate K48- and K63-linked substrate poly-ubiquition. TRIMs play part in positive and negative regulation of pattern recognition receptors (PRRs) of the innate immune system such as RLRs, TLRs, NLRs and C-type lectin receptors (CLRs) amongst others [72]. These receptors detect viral infection and then activate TRIM-mediated antiviral response by induction of pro-inflammatory cytokines, type I interferon and TNFα. Remarkably, primary involvement of TRIMs in immune response against viral pathogens resulted in these pathogens acquiring a range of sophisticated mechanisms to overcome the host immune system that includes hijacking host ubiquitination pathway and targeting TRIM family ligases, in particular. [73].