Dataset Information

OTUD7B controls non-canonical NF-?B activation through deubiquitination of TRAF3.

ABSTRACT: The non-canonical NF-?B pathway forms a major arm of NF-?B signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival. Activation of the non-canonical NF-?B 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-?B pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-?B activation but causes hyperactivation of non-canonical NF-?B. In response to non-canonical NF-?B stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-?B 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-?B activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.

SUBMITTER: Hu H

PROVIDER: S-EPMC3578967 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3.

Hu Hongbo H Brittain George C GC Chang Jae-Hoon JH Puebla-Osorio Nahum N Jin Jin J Zal Anna A Xiao Yichuan Y Cheng Xuhong X Chang Mikyoung M Fu Yang-Xin YX Zal Tomasz T Zhu Chengming C Sun Shao-Cong SC

Nature 20130120 7437

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 ...[more]

PMID: 23334419

Similar Datasets

Project description:STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor ?B (NF-?B) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in response to STING activation by double-stranded DNA (dsDNA). Furthermore, TANK-binding kinase 1 (TBK1) associated with STING was found to facilitate dsDNA-mediated canonical activation of NF-?B as well as IRF3 to promote proinflammatory gene transcription. The triggering of NF-?B function was noted to require TRAF6 activation. Our findings detail a novel dsDNA-mediated NF-?B activation pathway facilitated through a STING-TRAF6-TBK1 axis and suggest a target for therapeutic intervention to plausibly stimulate antiviral activity or, alternatively, avert dsDNA-mediated inflammatory disease.The IKK complex, which is composed of two catalytic subunits, IKK? and IKK?, has been suggested to be essential for the activation of canonical NF-?B signaling in response to various stimuli, including cytokines (e.g., interleukin-1? [IL-1?] and tumor necrosis factor alpha [TNF-?]), Toll-like receptor (TLR) ligands (e.g., lipopolysaccharide [LPS]), and dsRNAs derived from viruses, or a synthetic analog. STING has been identified as a critical signaling molecule required for the detection of cytosolic dsDNAs derived from pathogens and viruses. However, little is known about how cytosolic dsDNA triggers NF-?B signaling. In the present study, we demonstrate that TBK1, identified as an IKK-related kinase, may predominantly control the activation of NF-?B in response to dsDNA signaling via STING through the IKK?? activation loop. Thus, our results establish TBK1 as a downstream kinase controlling dsDNA-mediated IRF3 and NF-?B signaling dependent on STING.

Dataset Information

OTUD7B controls non-canonical NF-?B activation through deubiquitination of TRAF3.

Publications

OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets