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. 2007 Dec 7;318(5856):1628-32.
doi: 10.1126/science.1145918. Epub 2007 Nov 8.

DUBA: a deubiquitinase that regulates type I interferon production

Nobuhiko Kayagaki  1 , Qui Phung, Salina Chan, Ruchir Chaudhari, Casey Quan, Karen M O'Rourke, Michael Eby, Eric Pietras, Genhong Cheng, J Fernando Bazan, Zemin Zhang, David Arnott, Vishva M Dixit
Affiliations

DUBA: a deubiquitinase that regulates type I interferon production

Nobuhiko Kayagaki et al. Science. .

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.

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