Title |
Dimerization and Ubiquitin Mediated Recruitment of A20, a Complex Deubiquitinating Enzyme
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Published in |
Immunity, April 2013
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DOI | 10.1016/j.immuni.2013.03.008 |
Pubmed ID | |
Authors |
Timothy T. Lu, Michio Onizawa, Gianna E. Hammer, Emre E. Turer, Qian Yin, Ermelinda Damko, Alexander Agelidis, Nataliya Shifrin, Rommel Advincula, Julio Barrera, Barbara A. Malynn, Hao Wu, Averil Ma |
Abstract |
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 NFκB 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 2% |
Germany | 1 | <1% |
Norway | 1 | <1% |
Belgium | 1 | <1% |
Unknown | 119 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 37 | 30% |
Researcher | 23 | 19% |
Student > Master | 14 | 11% |
Student > Doctoral Student | 11 | 9% |
Student > Bachelor | 8 | 6% |
Other | 17 | 14% |
Unknown | 14 | 11% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 39 | 31% |
Biochemistry, Genetics and Molecular Biology | 35 | 28% |
Immunology and Microbiology | 17 | 14% |
Medicine and Dentistry | 8 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 2% |
Other | 8 | 6% |
Unknown | 14 | 11% |