title: The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3.
abstract: Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein. Specially, YopM associates with NLRP3, and its CLD ligase motif mediates the activating K63-linked ubiquitylation of NLRP3; as a result, YopM modulates NLRP3-mediated cell necrosis. Mutation of YopM E3 ligase motif dramatically reduces the ability of Y. pestis to induce HMGB1 release and cell necrosis, which ultimately contributes to bacterial virulence. In conclusion, this study has identified a previously unrecognized role for YopM E3 ligase activity in the regulation of host cell necrosis and plague pathogenesis.
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Congwen
authors.initials: C
authors.lastname: Wei
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Zongmin
authors.initials: Z
authors.lastname: Du
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Guan
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.|Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Feixiang
authors.initials: F
authors.lastname: Wu
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.|The General Hospital of Chinese People's Armed Police Forces, Beijing, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Chen
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Penghao
authors.initials: P
authors.lastname: Wang
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Zirui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Ruifu
authors.initials: R
authors.lastname: Yang
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D058947:Bacterial Secretion Systems; D005260:Female; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009336:Necrosis; D010930:Plague / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011485:Protein Binding; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014774:Virulence; D015010:Yersinia pestis / Q000201:enzymology* / Q000472:pathogenicity
chemical_list: D001425:Bacterial Outer Membrane Proteins; D058947:Bacterial Secretion Systems; D024243:HMGB1 Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C060772:yopM protein, Yersinia; D044767:Ubiquitin-Protein Ligases; D008239:Lysine