The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis

被引：245

作者：

Onizawa, Michio ^{[1
]}

Oshima, Shigeru ^{[1
]}

Schulze-Topphoff, Ulf ^{[2
]}

Oses-Prieto, Juan A. ^{[3
]}

Lu, Timothy ^{[1
]}

Tavares, Rita ^{[1
]}

Prodhomme, Thomas ^{[2
]}

Duong, Bao ^{[1
]}

Whang, Michael I. ^{[1
]}

Advincula, Rommel ^{[1
]}

Agelidis, Alex ^{[1
]}

Barrera, Julio ^{[1
]}

Wu, Hao ^{[4
]}

Burlingame, Alma ^{[3
]}

Malynn, Barbara A. ^{[1
]}

Zamvil, Scott S. ^{[2
]}

Ma, Averil ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA

[4] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Biol Chem & Mol Pharmacol,Program Cellular &, Boston, MA 02115 USA

来源：

NATURE IMMUNOLOGY | 2015年 / 16卷 / 06期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; LINEAR POLYUBIQUITIN; PROGRAMMED NECROSIS; EXPRESSION; TNFAIP3; INFLAMMATION; REGULATOR; BINDING; RECOGNITION; DOWNSTREAM;

D O I：

10.1038/ni.3172

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：618 / +

页数：11

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