Deubiquitylation and regulation of the immune response

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Abstract
Ubiquitylation is a reversible process that is counter-regulated by ubiquitylating and enzymes deubiquitylating enzymes (DUBs). In addition to targeting proteins for degradation by the 26S proteasome, ubiquitylation also mediates various non-degradative functions, including the regulation of protein trafficking and signal transduction. DUBs form a large family of proteases that de-conjugate ubiquitin chains from target proteins and thereby regulate diverse aspects of immune function, including innate immune responses to viruses and bacteria, the development and activation of lymphocytes, and the maintenance of immunological tolerance. The substrate binding of some DUBs, such as A20 and CYLD, involves specific adaptor proteins, which probably contribute to the functional diversity and specificity of the DUBs. These adaptor proteins often contain a ubiquitin-association domain that can bind to target proteins conjugated with ubiquitin chains. A20 has a crucial role in the negative regulation of innate immune-receptor signalling and prevention of inflammation. A20-deficient cells have a defect in terminating the NF-κB activation signal that is elicited from the tumour-necrosis-factor receptor and Toll-like receptors, which is associated with aberrant production of pro-inflammatory mediators. DUBA is a DUB that specifically regulates antiviral innate immune responses. DUBA deubiquitylates TRAF3 (tumour-necrosis factor (TNF) receptor (TNFR)-associated factor 3), an adaptor that connects the antiviral effector kinases, TBK1 (TANK-binding kinase 1) and IKKε (IκB (inhibitor of nuclear factor-κB (NF-κB)) kinase ε), to upstream signalling molecules. The DUBA-mediated deubiquitylation of TRAF3 might negatively regulate the recruitment and activation of TBK1–IKKε. CYLD has a crucial role in regulating the development, activation and homeostasis of T and B cells. In addition to negatively regulating NF-κB activation, CYLD has a positive role in thymocyte T-cell receptor signalling by deubiquitylating the protein tyrosine kinase LCK. Balanced events of ubiquitylation and deubiquitylation are required for the maintenance of T-cell tolerance and prevention of autoimmunity. Characterization of the DUBs that are involved in the induction of T-cell tolerance might be important for the rational design of new therapeutic approaches for treating autoimmune disorders.