title: DUBA: a deubiquitinase that regulates type I interferon production.
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.
authors.affiliation: Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Qui
authors.initials: Q
authors.lastname: Phung
authors.forename: Salina
authors.initials: S
authors.lastname: Chan
authors.forename: Ruchir
authors.initials: R
authors.lastname: Chaudhari
authors.forename: Casey
authors.initials: C
authors.lastname: Quan
authors.forename: Karen M
authors.initials: KM
authors.lastname: O'Rourke
authors.forename: Michael
authors.initials: M
authors.lastname: Eby
authors.forename: Eric
authors.initials: E
authors.lastname: Pietras
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D016898:Interferon-alpha / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495344:TLR3 protein, human; D048008:TNF Receptor-Associated Factor 3; D051196:Toll-Like Receptor 3; D025801:Ubiquitin; D010450:Endopeptidases; C525076:OTUD5 protein, human