DUBA: a deubiquitinase that regulates type I interferon production |
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Authors: | Kayagaki Nobuhiko Phung Qui Chan Salina Chaudhari Ruchir Quan Casey O'Rourke Karen M Eby Michael Pietras Eric Cheng Genhong Bazan J Fernando Zhang Zemin Arnott David Dixit Vishva M |
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Institution: | Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. |
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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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