On May 20, 2019, Dr. Yongqun Zhu laboratory published a research paper in Nature Microbiology entitled “A bacterial effector deubiquitinase specifically hydrolyses linear ubiquitin chains to inhibit host inflammatory signalling”, which describes that a unique bacterial deubiquitinase specifically cleaves host linear ubiquitin chains and addressed a long-term question in bacterial pathogenesis.
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.
Muyang Wan and Xiaofei Wang are the first authors, and Dr. Yongqun Zhu is the corresponding author of this paper. This study was supported by grants from China Ministry of Science and Technology, National Natural Science Foundation of China, the National High-level Talents Special Support Plan, the leading scientist program of Zhejiang High-level Talents Special Support Plan and the Fundamental Research Funds for the Central Universities.
