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Published Online November 8, 2007
Science DOI: 10.1126/science.1145918

Reports

Submitted on May 31, 2007
Accepted on October 30, 2007

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. Dixit 1*

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.
Vishva M. Dixit , E-mail: dixit{at}gene.com

Production of type I interferons (IFN-I) is a critical host defense triggered by pattern-recognition receptors (PRRs) of the innate immune system. DUBA, an ovarian tumor (OTU) domain-containing deubiquitinating enzyme, was discovered in a siRNA-based screen as a regulator of IFN-I production. Knockdown of DUBA augmented the PRR-induced IFN-I response, whereas ectopic expression of DUBA had the converse effect. DUBA bound 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 the kinase TBK1. A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of IFN-I. In sum, our data identify DUBA as a negative regulator of innate immune responses.


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