Publication Date:
2013-01-22
Description:
The non-canonical NF-kappaB pathway forms a major arm of NF-kappaB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival. Activation of the non-canonical NF-kappaB 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-kappaB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-kappaB activation but causes hyperactivation of non-canonical NF-kappaB. In response to non-canonical NF-kappaB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-kappaB 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-kappaB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578967/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578967/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Hongbo -- Brittain, George C -- Chang, Jae-Hoon -- Puebla-Osorio, Nahum -- Jin, Jin -- Zal, Anna -- Xiao, Yichuan -- Cheng, Xuhong -- Chang, Mikyoung -- Fu, Yang-Xin -- Zal, Tomasz -- Zhu, Chengming -- Sun, Shao-Cong -- AI057555/AI/NIAID NIH HHS/ -- AI064639/AI/NIAID NIH HHS/ -- CA137059/CA/NCI NIH HHS/ -- GM84459/GM/NIGMS NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA137059/CA/NCI NIH HHS/ -- R01 GM084459/GM/NIGMS NIH HHS/ -- T32 CA009598/CA/NCI NIH HHS/ -- T32CA009598/CA/NCI NIH HHS/ -- England -- Nature. 2013 Feb 21;494(7437):371-4. doi: 10.1038/nature11831. Epub 2013 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23334419" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
B-Lymphocytes/immunology/metabolism
;
Bacteria/immunology
;
Cells, Cultured
;
Endopeptidases/deficiency/genetics/*metabolism
;
Female
;
Fibroblasts
;
HEK293 Cells
;
Homeostasis
;
Humans
;
Intestines/immunology
;
Male
;
Mice
;
NF-kappa B/*metabolism
;
Proteolysis
;
Receptors, Cell Surface/metabolism
;
TNF Receptor-Associated Factor 3/*metabolism
;
*Ubiquitination
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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