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Science 327 (5969): 1135-1139

Copyright © 2010 by the American Association for the Advancement of Science

Inhibition of NF-{kappa}B Signaling by A20 Through Disruption of Ubiquitin Enzyme Complexes

Noula Shembade,1,* Averil Ma,2 Edward W. Harhaj1,*

Abstract: A20 negatively regulates inflammation by inhibiting the nuclear factor {kappa}B (NF-{kappa}B) transcription factor in the tumor necrosis factor–receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFR1 by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-{kappa}B signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c. A20, together with the regulatory molecule TAX1BP1, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest mechanism of A20 action in the inhibition of inflammatory signaling pathways.

1 Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
2 Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA.

* To whom correspondence should be addressed. E-mail: nshembade{at}med.miami.edu (N.S.); eharhaj{at}med.miami.edu (E.W.H.)


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