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A Deubiquitinase That Regulates Type I Interferon Production

Science, 7 December 2007
Vol. 318, Issue 5856, p. 1628-1632
DOI: 10.1126/science.1145918

A Deubiquitinase That Regulates Type I Interferon Production

  1. Nobuhiko Kayagaki1,
  2. Qui Phung2,
  3. Salina Chan1,
  4. Ruchir Chaudhari1,
  5. Casey Quan1,
  6. Karen M. O'Rourke1,
  7. Michael Eby1,
  8. Eric Pietras3,
  9. Genhong Cheng3,
  10. J. Fernando Bazan4,
  11. Zemin Zhang5,
  12. David Arnott2,
  13. Vishva M. Dixit1,*
  1. 1 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
  2. 2 Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
  3. 3 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
  4. 4 Department of Protein Engineering, Genentech, South San Francisco, CA 94080, USA.
  5. 5 Department of Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
  1. * To whom correspondence should be addressed. E-mail: dixit{at}gene.com

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.

  • Received for publication 31 May 2007.
  • Accepted for publication 30 October 2007.

Citation:

N. Kayagaki, Q. Phung, S. Chan, R. Chaudhari, C. Quan, K. M. O'Rourke, M. Eby, E. Pietras, G. Cheng, J. F. Bazan, Z. Zhang, D. Arnott, and V. M. Dixit, A Deubiquitinase That Regulates Type I Interferon Production. Science 318, 1628-1632 (2007).

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