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  • br GRAIL family Gene related to anergy in lymphocytes

    2021-05-11


    GRAIL family Gene related to anergy in lymphocytes protein (GRAIL, encoded by Rnf128 gene) is a transmembrane RING-type E3 ligase involved in T cell anergy and tolerance, and also regulation of smad pathway cytoskeletal organization [52]. This E3 was initially identified in CD4+ T helper cells and CD4+CD25+ regulatory T cells as an upregulated transcript that was later linked to immunosuppression [53,54]. GRAIL is an essential component of CD4+ T-cell tolerance and induction of anergic phenotype, a state of T cell unresponsiveness to antigenic stimulation that inhibits interleukin production [55,56]. GRAIL overexpression in CD4+ T cells has been clinically linked to Crohn’s disease, an inflammatory bowel disorder [57]. In addition, GRAIL regulates T cell tolerance and functions by mediating ubiquitination and proteasomal degradation of TCR-CD3 [55]. Activated GRAIL-deficient naive T cells enhance cytokine expression and proliferation, retard downregulation of TCR-CD3 expression and reduce hyper-responsiveness to TCR stimulation. Lower immunosuppressive capacity of GRAIL-deficient Treg cells was linked to overexpression of Th17-specific genes. In agreement with this, GRAIL-deficient mice had higher susceptibility to autoimmunity due to impaired induction of T cell tolerance. Another important GRAIL substrates include actin-related protein 2/3 subunit 5 (Arp2/3–5) and coronin 1 A, both associated with actin cytoskeleton organization and dynamics [58]. Arp2/3–5 and coronin 1 A levels were found to be significantly downregulated in GRAIL-overexpressing and anergic T cells. GRAIL also promotes innate antiviral immunity to RNA and DNA viruses via ubiquitination of TBK1, serine/threonine-protein kinase essential for production of IFNβ [59]. Recent data suggests that GRAIL absence can lead to anti-tumor activity of CD8+ cytotoxic T cells, essential for maintenance of anti-tumor processes [60]. Rnf128 gene (encoding GRAIL ubiquitin ligase) expression was upregulated in CD8+ T cells infiltrated into lymphoma tumors. Additional experiments demonstrated that GRAIL-deficiency enhances anti-tumor potency of CD8+ T cells, and contributes to long-term regulation of tumorigenesis and capability to repress existing tumors. The same study proposed IL-21R as another GRAIL substrate, confirming previous data on involvement of GRAIL in negative regulation of IL-21 mediated by NFATc1 transcription factor [55]. GRAIL overexpression and IL-21R downregulation was observed in CD8+ T cells isolated from lymphoma patients as compared to samples from healthy donors. On the opposite, loss of GRAIL in lymphoma patients resulted in enhanced infiltration of GRAIL-deficient CD8+ T cells with IL-21R overexpression in turn leading to high IL-21 responsiveness [60].
    TRAF family Tumor necrosis factor (TNF) receptor associated factor (TRAF) family of proteins includes seven members, TRAF1-TRAF7, that control many biological processes, including regulation of innate and adaptive immune functions, homeostasis, cytokine production and cell survival [61]. TRAF family members contain several zing finger motifs and share high sequence homology in C-terminal TRAF domain, also all of them (except TRAF1) contain N-terminal RING finger domain that confers E3 ubiquitin ligase activity. Adaptor functions and E3 ubiquitin-ligating activity of TRAF proteins allows them to mediate transduction of downstream signaling. Ubiquitination is considered as a primary mechanism of TRAF signaling that is conducted via catalysis of non-degradative K63-linked poly-ubiquitination of their substrates, such as various receptors, kinases and transcription factors [62]. In the past decade TRAFs have been recognized as signal transducers for a broad range of receptor families engaged in innate and smad pathway adaptive immune signaling and cytokine production. Several primary receptor classes currently known to be involved in TRAF signal transduction include T cell receptor, Toll-like receptors (TLRs), NOD-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), IFN receptors, TGFβ receptors, IL-1 and IL-17 receptors [62]. TRAF-dependent signaling pathway leads to activation of mitogen-activated protein kinases (MAPKs), interferon-regulatory factors (IRFs) and, most importantly, key transcription factors such as NF-κB and activator protein 1 (AP-1) that are responsible for expression of multiple genes associated with inflammation and immune response.