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

Proceedings of the National Academy of Sciences of the United States of America
Jevgenia Zilberman-RudenkoEric P Hanson

Abstract

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 cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB 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-κB 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-κB activation by NEMO, and its absence results in autoinflammatory disease.

References

Apr 22, 2004·The Journal of Allergy and Clinical Immunology·Jordan S OrangeFrancisco A Bonilla
Sep 10, 2004·The Journal of Allergy and Clinical Immunology·Jordan S OrangeRaif S Geha
Dec 8, 2005·American Journal of Medical Genetics. Part a·Karen Helene ØrstavikJon Steen-Johnsen
Jul 5, 2006·The Journal of Experimental Medicine·Orchidée Filipe-SantosJean-Laurent Casanova
Mar 16, 2007·Nature·Arianna NenciManolis Pasparakis
Jan 27, 2009·Nature Genetics·Rajan P NairUNKNOWN Collaborative Association Study of Psoriasis
Apr 21, 2009·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Laurence E ChengDiane W Wara
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Owen M SiggsBruce Beutler
Mar 20, 2010·Cold Spring Harbor Perspectives in Biology·Alain Israël
Mar 23, 2010·Cell·Daniel L KastnerRaphaela Goldbach-Mansky
May 12, 2010·Cold Spring Harbor Perspectives in Biology·Toby Lawrence
Jun 10, 2010·The Journal of Experimental Medicine·Lars VereeckeGeert van Loo
Nov 26, 2010·Molecular Cell·Ivan BosanacSarah G Hymowitz
May 31, 2011·The Journal of Biological Chemistry·Kamyar HadianDaniel Krappmann
Jul 21, 2011·Nature Immunology·Jürgen Ruland
Nov 22, 2011·Molecular Cell·Brian SkaugZhijian J Chen
Feb 21, 2013·PloS One·Rosemarie SeymourJohn P Sundberg

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Citations

Dec 17, 2016·Cell·Junying YuanBénédicte F Py
Jan 25, 2017·The Journal of Allergy and Clinical Immunology·Meri KaustioMikko Seppänen
Jul 20, 2017·Nature Immunology·Inna S AfoninaRudi Beyaert
Aug 6, 2019·Scandinavian Journal of Immunology·Jacek Hawiger, Jozef Zienkiewicz
Oct 31, 2019·Rheumatology·Albin BjörkMarie Wahren-Herlenius
Sep 25, 2020·Cell Death & Disease·Jinyuan MaWeinan Guo
Mar 30, 2018·Genes & Development·Bing ShanJunying Yuan
Sep 23, 2020·Arthritis Research & Therapy·Yongyao WuBin Shao
Feb 13, 2016·Nature Reviews. Rheumatology·Joana Osório
Sep 6, 2020·Scandinavian Journal of Immunology·Sandro F PerazzioMikko R J Seppänen
Aug 28, 2020·Biochimica Et Biophysica Acta. Proteins and Proteomics·Myung Soo KoTom Huxford
Jul 21, 2021·Journal of Neurogenetics·Owen Davis SandersJayalekshmi Archa Rajagopal
Jun 11, 2021·Journal of the American Society of Nephrology : JASN·Shelby Reid, James W Scholey
Aug 27, 2021·Frontiers in Immunology·Laura BarnabeiRobert Weil
Nov 24, 2021·Annual Review of Genetics·Daichao XuJunying Yuan

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