A bacterial effector deubiquitinase specifically hydrolyses linear ubiquitin chains to inhibit host inflammatory signalling
- 20 May 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 4 (8), 1282-1293
- https://doi.org/10.1038/s41564-019-0454-1
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.Keywords
This publication has 51 references indexed in Scilit:
- OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked PolyubiquitinCell, 2013
- SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosisNature, 2011
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa Crystallographica Section D-Structural Biology, 2010
- XDSActa Crystallographica Section D-Structural Biology, 2010
- E2 interaction and dimerization in the crystal structure of TRAF6Nature Structural & Molecular Biology, 2009
- The Legionella pneumophila replication vacuole: making a cosy niche inside host cellsNature Reviews Microbiology, 2008
- SseL, a Salmonella deubiquitinase required for macrophage killing and virulenceProceedings of the National Academy of Sciences of the United States of America, 2007
- A ubiquitin ligase complex assembles linear polyubiquitin chainsThe EMBO Journal, 2006
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997