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  • br E Ubiquitin Ligases Regulate Central and


    E3 Ubiquitin Ligases Regulate Central and Peripheral T Cell Tolerance During the random process of somatic recombination, T cell receptors (TCRs; see Glossary) that recognize self-antigens are commonly generated. Notably, meticulously precise filtering mechanisms, termed tolerance, are necessary to eliminate or inactivate these self-reactive T Talabostat mesylate to prevent autoimmunity. Establishment of T cell tolerance starts during T cell development in the thymus (central tolerance) and is maintained in the periphery (peripheral tolerance). During T cell development, T cells are first positively selected by their ability to bind to major histocompatibility complex (MHC)–peptide complexes presented by cortical thymic epithelial cells (cTECs). T cells that cannot bind to peptide/MHC complexes undergo death by neglect, whereas those that can bind survive and progress towards the next developmental stage where tolerance is established by negative selection [15]. Medullary thymic epithelial cells (m)TECs and dendritic cells (DCs) present an array of self-peptides associated with major MHC class I or II molecules, and T cells that express TCRs with high-affinity binding to self-peptide/MHC complexes undergo apoptosis (clonal deletion), whereas those with intermediate TCR affinity differentiate into natural regulatory T cells (nTreg; clonal diversion) which, together with CD4+ and CD8+ T cells with low affinity for the self-peptide/MHC complexes, exit the thymus and seed the periphery (Figure 1A). The E3 ligase, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), functions in the development and distribution of mTECs in the thymic stroma. TRAF6 inactivation in mice promotes multiorgan autoimmunity [16], whereas TEC-specific deletion of TRAF6 results in a narrow spectrum of autoimmunity, only affecting the liver [17]. Although the TEC-specific deletion clearly illustrates a role for TRAF6 in negative selection, the more limited autoimmune manifestation as compared to systemic TRAF6 loss also highlights that additional tolerance mechanisms in the periphery limit autoimmunity when central tolerance fails. Peripheral tolerance is mediated by one of three mechanisms, namely activation-induced cell death (AICD), promotion of anergy, and suppression by Treg (Figure 1A). As outlined below, E3s function in all of these activities, and many serve to prevent autoimmunity (Table 1, Key Table).
    E3 Ubiquitin Ligase Function in Innate Immune Cells Affects T Cell Responses
    E3 Ubiquitin Ligases in Tumor Immunosurveillance and Escape By analogy to autoimmunity, the contribution of E3s to tumor immunosurveillance extends beyond their role in immune cells and includes important regulatory roles in the tumor stroma and the tumor itself. These mechanisms collectively impact on T cell dysfunction within or exclusion from the TME – the two major mechanisms of tumor immune escape [67] (Figure 2).
    E3 Ubiquitin Ligases in Balancing Autoimmunity and Antitumor Immunity – Therapeutic Implications Many factors that restrain autoimmunity (such as PD-1/PD-L1, CTLA-4, and TGF-β) are equally relevant to cancer therapy because they may be targeted to promote tumor eradication. Because several E3s function as negative regulators of immune responses (Table 1), and some have been demonstrated to also regulate immunosurveillance in the TME (Figure 2), targeting E3s may represent a promising approach to boost antitumor immune responses. Since multiple inhibitory pathways in the TME (e.g., PD-L1 79, 80, TGF-β [78], and Treg 70, 71) use the same E3 ligase (e.g., Cbl-B) as the downstream signaling effector to inhibit T cell effector function, one may speculate that targeting T cell-intrinsic checkpoints (e.g., Cbl-B) may be more efficient in activating antitumor immune responses than targeting individual cell-surface inhibitory receptors. Although targeting E3s remains a more challenging task, technological advances (e.g., CRISPR gene editing and harnessing synthetic gene circuits [89]), a better biological understanding of their mode of action (e.g., systematic mapping of degrons, the specific motifs in substrates that are recognized by the E3 90, 91) as well as advances in compound screening now allow one to envision an efficient way to target E3 ligases in the near future: such approaches may include genetic engineering of T cells for adoptive cell transfer [92] or chimeric antigen receptor (CAR) T cell therapy, and efforts to identify small molecule inhibitors such as for Cbl-B are ongoing 93, 94. E3 themselves or their substrates could also be targeted by a protein targeting complex approach (PROTAC), which directs a substrate to a E3 ligase by chemical linkers [95]. In addition to Cbl-B and Grail, other ubiquitin ligases that function in autoimmunity (such as Itch, Peli1, Roquin, and RNF5) may regulate stroma-mediated antitumor immunity and may thus serve as putative therapeutic targets to promote antitumor immunity. With that noted, we recognize that a better understanding of E3 function in distinct tissues will be required, and further improvements in the therapeutic targeting of protein–protein interactions will be necessary to move E3-targeting therapies into the clinic.