![]() ![]() It is noteworthy that E3 ligase may also cause altered activity or subcellular re-localization of target proteins. Hence, depending on the tumorigenic properties of specific substrates, E3 ligases play a context-dependent role by degrading tumor suppressors or oncoproteins 19, 20. E3 ligases are involved in the final enzymatic activity leading to ubiquitination and dictates the specificity of substrate selection. For instance, increased generation of MHC Class I antigen HLA (human leukocyte antigen)-B27 closely correlates to Ankylosing Spondylitis 15, 16.ĭysregulation of the UPS is associated with tumorigenic events 17, 18. Autoimmune diseases are often induced by the mis-recognition of endogenous proteins as exogenous antigens 14, which was tightly controlled by the UPS. Pathologically, neurodegenerative disorders often feature the accumulation of misfolded proteins, such as tau aggregates and Aβ plaques in Alzheimer’s disease 12, 13. Dysregulation of the UPS is involved in the pathogenesis of multiple disorders, especially neurodegeneration, neoplastic transformation and autoimmune diseases 11. Meanwhile, via proteasomal cleavage of endogenous proteins, the UPS governs the production of MHC (major histocompatibility complex) Class I antigens, which are critical for the functions of the immune response 9, 10. In addition, proteolytic activities provide necessary raw materials for intracellular recycling and rebuilding, such as generation of amino acids 6, 8. For instance, proteasomal degradation of cell cycle regulators, such as p21 and p27, is a critical to control cell cycle progression 6. Physiological significance and pathological roles of the UPSĬonsistent with a broad central role that the UPS plays in proteostatic control, nearly every aspect of cellular biology is regulated in some manner by the UPS pathway, especially the cell cycle, cell growth, immune homeostasis, and metabolic stability 6. Additionally, E3 ligases also mediate the attachment of the ubiquitin moiety to existing ubiquitin chains on a substrate protein, resulting in poly-ubiquitination and diverse consequences to the target protein, such as degradation 2, 6, altered activity, or subcellular localization of substrates 7. Subsequently, E3 ligase determines the substrate specificity and facilitates the formation of a covalent isopeptide bond between the ubiquitin and lysine residues of target proteins, leading to substrate ubiquitination. As a result, activated ubiquitin is then transferred to an E2 conjugating enzyme, which then assist in the recruitment of an E3 ligase into a complex with the ubiquitin moiety. Briefly, the ATP-dependent activation of ubiquitin by the E1 activating enzyme is indispensable for the initiation of the enzymatic cascade 5. The machinery of the ubiquitin-proteasome cascade has been reviewed extensively 3, 4. ![]() The UPS generally consists of ubiquitin, ubiquitination enzymes and the 26S proteasome, which synergistically form an enzymatic cascade to transfer ubiquitin in a substrate-specific manner to promote subsequent proteolysis and degradation of the target protein 2. The ubiquitin-proteasome system (UPS) is an evolutionarily conserved apparatus that serves as a major regulator of proteostasis in eukaryotic cells 1. The anti-tumor effects using the PROTAC approach to target the degradation of undruggable targets are also highlighted. We summarize the recent major advances in the CRL4 research field towards understanding its involvement in tumorigenesis and further discuss its clinical implications. To this end, PROTACs have been developed as a group of engineered bi-functional chemical glues that induce the ubiquitination-mediated degradation of substrates via recruiting E3 ligases, such as CRL4 (CRBN) and CRL2 (pVHL). Notably, targeting CRL4 has recently emerged as a noval anti-cancer strategy, including thalidomide and its derivatives that bind to the substrate recognition receptor cereblon (CRBN), and anticancer sulfonamides that target DCAF15 to suppress the neoplastic proliferation of multiple myeloma and colorectal cancers, respectively. Based on evidence from knockout and transgenic mouse models, human clinical data, and biochemical interactions, we summarize the distinct roles of the CRL4 E3 ligase complexes in tumorigenesis, which appears to be tissue- and context-dependent. As a member of the Cullin-RING ligase family, Cullin-RING ligase 4 (CRL4) has drawn much attention due to its broad regulatory roles under physiological and pathological conditions, especially in neoplastic events. ![]()
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