The Ubiquitin-modifying Enzyme A20 Restricts Ubiquitination of the Kinase RIPK3 and Protects Cells from Necroptosis

Overview

Journal Nat Immunol

Date 2015 May 5

PMID 25939025

Citations 166

Authors

Michio Onizawa

Shigeru Oshima

Ulf Schulze-Topphoff

Juan A Oses-Prieto

Timothy Lu

Rita Tavares

Thomas Prodhomme

Bao Duong

Michael I Whang

Rommel Advincula

Alex Agelidis

Julio Barrera

Hao Wu

Alma Burlingame

Barbara A Malynn

Scott S Zamvil

Averil Ma

Affiliations

Soon will be listed here.

Abstract

A20 is an anti-inflammatory protein linked to multiple human diseases; however, the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We found that A20-deficient T cells and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. Global deficiency in RIPK3 significantly restored the survival of A20-deficient mice. A20-deficient cells exhibited exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 underwent physiological ubiquitination at Lys5 (K5), and this ubiquitination event supported the formation of RIPK1-RIPK3 complexes. Both the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex required the catalytic cysteine of A20's deubiquitinating motif. Our studies link A20 and the ubiquitination of RIPK3 to necroptotic cell death and suggest additional mechanisms by which A20 might prevent inflammatory disease.

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