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OTUD7B controls non-canonical NF-kB activation through deubiquitination of TRAF3
( Hongbo Hu ),( George C Brittain ),( Jae Hoon Chang ),( Nahum Puebla Osorio ),( Jin Jin ),( Anna Zal ),( Yichuan Xiao ),( Xuhong Cheng ),( Mikyoung Chang ),( Yang Xin Fu ),( Tomasz Zal ),( Chengming 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
The non-canonical NF-κB pathway forms a major arm of NF-κB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival. Activation of the non-canonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3), but how this signalling event is controlled is still unknown. Here we have identified the deubiquitinase OTUD7B as a pivotal regulator of the non-canonical NF-κB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyperactivation of non-canonical NF-κB. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. Consequently, the OTUD7Bdeficiency results in B-cell hyper-responsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defence ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish OTUD7B as a crucial regulator of signal-inducednon-canonical NF-κB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.
( Jia Yi Yu ),( Xiao Fei Zhou ),( Mi Kyoung Chang ),( Mako Nakaya ),( Jae Hoon Chang ),( Yi Chuan Xiao ),( J. William Lindsey ),( Stephanie Dorta Estremera ),( Wei Cao ),( Anna Zal ),( Tomasz Zal ),( 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draininglumph node in a neuroinflammatory autoimmunity model,experimental autoimmune encephalomyelitis (EAE).Atolder ager,the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype.TBK1 contrlos the activation of AKT and its downsream kinase m TIORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor fo TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis.