免疫(IMMUNITY)2013-09-05 2:57 AM

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

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 (Tnfaip3OTU mice) or A20’s ZF4 (Tnfaip3ZF4 mice). Both Tnfaip3OTU and Tnfaip3ZF4 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. A20OTU proteins and A20ZF4 proteins complemented each other to regulate RIP1 ubiquitination and NFκB signaling normally in compound mutant Tnfaip3OTU/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.

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