title: Yersinia YopJ negatively regulates IRF3-mediated antibacterial response through disruption of STING-mediated cytosolic DNA signaling.
abstract: The Yersinia outer protein J (YopJ) plays a pivotal role in evading the host immune response and establishes a persistent infection in host cells after bacterial infection. YopJ is a cysteine protease and can act as a deubiquitinating enzyme that deubiquitinates several targets in multiple signaling pathways. Stimulator of interferon genes (STING) is a critical adapter for the induction of interferon regulatory factor 3 (IRF3) phosphorylation and subsequent production of the cytokines in response to nucleic acids in the cytoplasm. Our studies demonstrate that YopJ targets STING to inhibit IRF3 signaling. Specially, YopJ interacts with STING to block its ER-to-Golgi traffic and remove its K63-linked ubiquitination chains. Deubiquited STING perturbs the formation of STING-TBK1 complex and the activation of IRF3. The 172th cysteine of YopJ mediated STING deubiquitination and IRF3 signaling inhibition. Consequently, mice infected with WT and ΔYopJ/YopJ bacteria induced lower levels of IRF3 and IFN-β, decreased inflammation and reduced staining of STING as compared to ΔYopJ and ΔYopJ/YopJ C172A strains infection. The data herein reveal a previously unrecognized mechanism by which YopJ modulates innate immune signaling.
authors.affiliation: Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, Jilin University, Changchun 130012, China; College of Life Science, Jilin University, Changchun 130012, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: caoye1987122@163.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: geminigk@aliyun.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: hexiang_spring@yahoo.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: weicw@yahoo.com.
authors.forename: Congwen
authors.initials: C
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: zirui_zheng@163.com.
authors.forename: Zirui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: yanhongzhang333@163.com.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, Jilin University, Changchun 130012, China; College of Life Science, Jilin University, Changchun 130012, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: shengli0128@163.com.
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: towall@yahoo.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, Jilin University, Changchun 130012, China; College of Life Science, Jilin University, Changchun 130012, China. Electronic address: shiw@jlu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D004247:DNA / Q000235:genetics* / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000382:microbiology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism / Q000382:microbiology; D057809:HEK293 Cells; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D054875:Ubiquitination; D015010:Yersinia pestis / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D000099197:STING Protein
chemical_list: D001426:Bacterial Proteins; D004247:DNA; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C109227:YopP protein, Yersinia; C498588:Tbk1 protein, mouse
keywords: Deubiquitination; IFN-β; IRF3; STING; Yop J