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Nat Microbiol. 2019 May 20. doi: 10.1038/s41564-019-0454-1. [Epub ahead of print]

A bacterial effector deubiquitinase specifically hydrolyses linear ubiquitin chains to inhibit host inflammatory signalling.

Author information

1
MOE Key Laboratory of Biosystems Homeostasis & Protection, Innovation Center for Cell Signalling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
2
Institute of Microbiology, College of Life Sciences, Zhejiang University, Hangzhou, China.
3
MOE Key Laboratory of Biosystems Homeostasis & Protection, Innovation Center for Cell Signalling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. zhuyongqun@zju.edu.cn.
4
Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. zhuyongqun@zju.edu.cn.

Abstract

Linear ubiquitin (Ub) chains regulate many cellular processes, including NF-κB immune signalling. Pathogenic bacteria have evolved to secrete effector proteins that harbour deubiquitinase activity into host cells to disrupt host ubiquitination signalling. All previously identified effector deubiquitinases hydrolyse isopeptide-linked polyubiquitin (polyUb). It has been a long-standing question whether bacterial pathogens have evolved an effector deubiquitinase to directly cleave linear Ub chains. In this study, we performed extensive screening of bacterial pathogens and found that Legionella pneumophila-the causative agent of human Legionnaire's disease-encodes an effector protein, RavD, which harbours deubiquitinase activity exquisitely specific for linear Ub chains. RavD hydrolyses linear Ub chains but not any type of isopeptide-linked polyUb. The crystal structure of RavD with linear diubiquitin reveals that RavD adopts a papain-like fold with a Cys-His-Ser catalytic triad. The Ub-binding surface and specific interacting residues in RavD determine its specificity for Met1 linkages. RavD prevents the accumulation of linear Ub chains on Legionella-containing vacuoles established by the pathogen in host cells to inhibit the NF-κB pathway during infection. This study identified a unique linear Ub chain-specific effector deubiquitinase and indicates its potential application as a tool to dissect linear polyUb-mediated signalling in mammalian cells.

PMID:
31110362
DOI:
10.1038/s41564-019-0454-1

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