title: OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3.
abstract: 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 OTUD7B deficiency 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-induced non-canonical NF-κB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.
authors: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors: Hongbo
authors: H
authors: Hu
authors: George C
authors: GC
authors: Brittain
authors: Jae-Hoon
authors: JH
authors: Chang
authors: Nahum
authors: N
authors: Puebla-Osorio
authors: Jin
authors: J
authors: Jin
authors: Anna
authors: A
authors: Zal
authors: Yichuan
authors: Y
authors: Xiao
authors: Xuhong
authors: X
authors: Cheng
authors: Mikyoung
authors: M
authors: Chang
authors: Yang-Xin
authors: YX
authors: Fu
authors: Tomasz
authors: T
authors: Zal
authors: Chengming
authors: C
authors: Zhu
authors: Shao-Cong
authors: SC
authors: Sun
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001419:Bacteria / Q000276:immunology; D002478:Cells, Cultured; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007422:Intestines / Q000276:immunology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D054875:Ubiquitination; D000072017:Deubiquitinating Enzymes
chemical_list: D010450:Endopeptidases; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D048008:TNF Receptor-Associated Factor 3; C578787:Otud7b protein, mouse; D000072017:Deubiquitinating Enzymes