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Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-?B activation and autoinflammatory disease.


ABSTRACT: Receptor-induced NF-?B activation is controlled by NEMO, the NF-?B essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (?CT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased I?B kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ?CT-NEMO mutants promoted increased NF-?B activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-?B activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-?B activation by NEMO, and its absence results in autoinflammatory disease.

SUBMITTER: Zilberman-Rudenko J 

PROVIDER: S-EPMC4760784 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease.

Zilberman-Rudenko Jevgenia J   Shawver Linda Monaco LM   Wessel Alex W AW   Luo Yongquan Y   Pelletier Martin M   Tsai Wanxia Li WL   Lee Younglang Y   Vonortas Spiridon S   Cheng Laurence L   Ashwell Jonathan D JD   Orange Jordan S JS   Siegel Richard M RM   Hanson Eric P EP  

Proceedings of the National Academy of Sciences of the United States of America 20160122 6


Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary  ...[more]

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