Ubiquitination is a crucial mechanism that regulates T-cell activation and T cell-mediated immune responses, and deregulated ubiquitination events are linked to human immunological disorders including autoimmunity and inflammation. A well-known function of ubiquitination is to control T cell receptor (TCR)-proximal signaling events by mediating ubiquitin-dependent degradation of CD3 and key signaling factors. Ubiquitination also regulates the fate or activation of downstream signaling molecules in the TCR pathway, in a positive or negative manner. Like phosphorylation, ubiquitination is a reversible process, in which ubiquitin chains are conjugated and deconjugated by ubiquitinating enzymes (E1, E2, E3) and deubiquitinases (DUBs), respectively. Despite the extensive studies of E3 ubiquitin ligases, the DUBs that regulate TCR signaling and T-cell functions are still poorly defined. The PI's laboratory has been in a leading position in this research area. During the previous funding cycles, we have made seminal findings demonstrating a crucial role for the DUB CYLD in regulating T-cell activation and autoimmune inflammation. Moreover, our recently published work and preliminary studies have led to the identification of several novel T cell-regulatory DUBs, which forms a solid foundation for this renewal application. Using biochemical and mouse genetic approaches, we have identified Otud7b as a DUB that positively regulates TCR-proximal signaling. Otud7b deficiency attenuates the activation of the TCR-proximal kinase Zap70 as well as multiple downstream signaling factors. Interestingly, in response to TCR/CD28 stimulation, Otud7b is rapidly recruited to CD3 and appears to regulate the stability of this TCR signaling chain. Based on these findings, we hypothesize that Otud7b may facilitate TCR signaling by regulating the ubiquitination of CD3 and possibly key TCR-proximal signaling factors. Our studies also led to the identification of two homologous DUBs of the USP family, Usp4 and Usp15, as negative regulators of T-cell activation. Interestingly, despite the strong homology of Usp4 and Usp15, genetic ablation of either of them causes hyper-activation of T cells. This finding raises the question of how these two highly homologous DUBs exert non-redundant signaling functions and whether they also have redundancies in some signaling functions. The overall objective of this continuation application is to understand the molecular mechanisms by which Otud7b and Usp4/Usp15 regulate TCR signaling and T cell-mediated immunity and autoimmune inflammation. To accomplish our overall objective, we will (1) define the molecular mechanism by which Otud7b mediates TCR signaling, (2) examine how Usp4 and USP15 negatively regulate TCR signaling, and (3) investigate in vivo functions of Otud7b and Usp4 in regulating T-cell function and autoimmune inflammation. We believe that these proposed studies are highly innovative and will yield high-impact findings that lead to a major advancement of the field. With the establishment of newly generated mouse models and our extensive experience, we are in a unique position to carry out the proposed project.
Ubiquitination is a crucial mechanism that regulates immune system functions, including T-cell activation, and deregulated ubiquitination events are linked to human immunological disorders such as infections, autoimmunity, and inflammation. The proposed project addresses innovative questions regarding how deubiquitinases regulate T-cell function and autoimmune inflammation.
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