title: Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation.
abstract: The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IkappaBalpha. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-kappaB signaling by selectively removing K63-linked polyubiquitin chains that activate IkappaB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IkappaBalpha. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ.
authors.affiliation: Molecular Oncology Department, Genentech, Inc., San Francisco, CA 94080, USA.
authors.forename: Honglin
authors.initials: H
authors.lastname: Zhou
authors.forename: Denise M
authors.initials: DM
authors.lastname: Monack
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wertz
authors.forename: Jianpin
authors.initials: J
authors.lastname: Yin
authors.forename: Beni
authors.initials: B
authors.lastname: Wolf
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D010450:Endopeptidases / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*; D037521:Virulence Factors / Q000737:chemistry / Q000502:physiology*; D015007:Yersinia / Q000201:enzymology* / Q000472:pathogenicity; D015009:Yersinia Infections / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D016328:NF-kappa B; D025842:SUMO-1 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D037521:Virulence Factors; C109227:YopP protein, Yersinia; D010450:Endopeptidases; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C091939:ubiquitin isopeptidase