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Science 318 (5856): 1628-1632

Copyright © 2007 by the American Association for the Advancement of Science

DUBA: A Deubiquitinase That Regulates Type I Interferon Production

Nobuhiko Kayagaki,1 Qui Phung,2 Salina Chan,1 Ruchir Chaudhari,1 Casey Quan,1 Karen M. O'Rourke,1 Michael Eby,1 Eric Pietras,3 Genhong Cheng,3 J. Fernando Bazan,4 Zemin Zhang,5 David Arnott,2 Vishva M. Dixit1*

Abstract: Production of type I interferon (IFN-I) is a critical host defense triggered by pattern-recognition receptors (PRRs) of the innate immune system. Deubiquitinating enzyme A (DUBA), an ovarian tumor domain-containing deubiquitinating enzyme, was discovered in a small interfering RNA–based screen as a regulator of IFN-I production. Reduction of DUBA augmented the PRR-induced IFN-I response, whereas ectopic expression of DUBA had the converse effect. DUBA bound tumor necrosis factor receptor–associated factor 3 (TRAF3), an adaptor protein essential for the IFN-I response. TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63–linked polyubiquitin chains. DUBA selectively cleaved the lysine-63–linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1. A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of IFN-I. Our data identify DUBA as a negative regulator of innate immune responses.

1 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
2 Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
3 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
4 Department of Protein Engineering, Genentech, South San Francisco, CA 94080, USA.
5 Department of Bioinformatics, Genentech, South San Francisco, CA 94080, USA.

* To whom correspondence should be addressed. E-mail: dixit{at}gene.com


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