Dimerization and Ubiquitin Mediated Recruitment of A20, a Complex Deubiquitinating Enzyme

被引：130

作者：

Lu, Timothy T. ^{[1
]}

Onizawa, Michio ^{[1
]}

Hammer, Gianna E. ^{[1
]}

Turer, Emre E. ^{[1
]}

Yin, Qian ^{[2
]}

Damko, Ermelinda ^{[2
]}

Agelidis, Alexander ^{[1
]}

Shifrin, Nataliya ^{[1
]}

Advincula, Rommel ^{[1
]}

Barrera, Julio ^{[1
]}

Malynn, Barbara A. ^{[1
]}

Wu, Hao ^{[2
]}

Ma, Averil ^{[1
]}

机构：

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

[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

来源：

IMMUNITY | 2013年 / 38卷 / 05期

关键词：

NF-KAPPA-B; ZINC-FINGER PROTEIN; SYSTEMIC-LUPUS-ERYTHEMATOSUS; POLYUBIQUITIN-BINDING; LINEAR POLYUBIQUITIN; RHEUMATOID-ARTHRITIS; EDITING ENZYME; ACTIVATION; ALPHA; TNF;

D O I：

10.1016/j.immuni.2013.03.008

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 autoimmune diseases and lymphomas. A20 possesses a deubiquitinating motif and a zinc finger, ZF4, that binds ubiquitin and supports its E3 ubiquitin ligase activity. To understand how these activities mediate A20's physiological functions, we generated two lines of gene-targeted mice, abrogating either A20's deubiquitinating activity (Tnfaip3(OTU) mice) or A20's ZF4 (Tnfaip3(ZF4) mice). Both Tnfaip3(OTU) and Tnfaip3(ZF4) mice exhibited increased responses to TNF and sensitivity to colitis. A20's C103 deubiquitinating motif restricted both K48- and K63-linked ubiquitination of receptor interacting protein 1 (RIP1). A20's ZF4 was required for recruiting A20 to ubiquitinated RIP1. A20 OTU proteins and A20(ZF4) proteins complemented each other to regulate RIP1 ubiquitination and NF kappa B signaling normally in compound mutant Tnfaip3(OTU/ZF4) cells. This complementation involved homodimerization of A20 proteins, and we have defined an extensive dimerization interface in A20. These studies reveal how A20 proteins collaborate to restrict TNF signaling.

引用

页码：896 / 905

页数：10

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