Publication Date:
2007-11-10
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- New York, N.Y. -- Science. 2007 Dec 7;318(5856):1628-32. Epub 2007 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17991829" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs
;
Amino Acid Sequence
;
Animals
;
Cell Line
;
Endopeptidases/*metabolism
;
Humans
;
Interferon Type I/*biosynthesis/genetics
;
Interferon-alpha/genetics
;
Molecular Sequence Data
;
NF-kappa B/metabolism
;
Protein Structure, Tertiary
;
RNA, Small Interfering
;
Signal Transduction
;
TNF Receptor-Associated Factor 3/metabolism
;
Toll-Like Receptor 3/metabolism
;
Ubiquitin/metabolism
;
Ubiquitination
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
