title: The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome.
abstract: Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation.
authors: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Center for Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors: Lawton K
authors: LK
authors: Chung
authors: Inflammatory Disease Section, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors: Yong Hwan
authors: YH
authors: Park
authors: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors: Yueting
authors: Y
authors: Zheng
authors: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Igor E
authors: IE
authors: Brodsky
authors: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors: Patrick
authors: P
authors: Hearing
authors: Inflammatory Disease Section, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors: Daniel L
authors: DL
authors: Kastner
authors: Inflammatory Disease Section, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors: Jae Jin
authors: JJ
authors: Chae
authors: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Center for Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: james.bliska@stonybrook.edu.
authors: James B
authors: JB
authors: Bliska
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D058847:Inflammasomes / Q000037:antagonists & inhibitors; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D000071198:Pyrin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism; D015011:Yersinia pseudotuberculosis / Q000276:immunology / Q000472:pathogenicity*; D015012:Yersinia pseudotuberculosis Infections / Q000382:microbiology / Q000473:pathology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D058847:Inflammasomes; C000604193:Mefv protein, mouse; D000071198:Pyrin; D037521:Virulence Factors; C116117:YopT protein, Yersinia; C063239:yopE protein, Yersinia; C060772:yopM protein, Yersinia; C061570:protein kinase N; D011493:Protein Kinase C; D003546:Cysteine Endopeptidases; D020742:rhoA GTP-Binding Protein