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Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-B activation

¹ Molecular Oncology Department, Genentech, Inc., San Francisco, CA 94080
² Protein Engineering Department, Genentech, Inc., San Francisco, CA 94080
³ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305

CORRESPONDENCE Vishva Dixit: dixit{at}gene.com

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 B (NF-B) 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 IB. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-B signaling by selectively removing K63-linked polyubiquitin chains that activate IB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IB. 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.

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