title: The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection.
abstract: Caspase-mediated inflammatory cell death acts as an intrinsic defense mechanism against infection. Bacterial pathogens deploy countermeasures against inflammatory cell death, but the mechanisms by which they do this remain largely unclear. In a screen for Shigella flexneri effectors that regulate cell death during infection, we discovered that Shigella infection induced acute inflammatory, caspase-4-dependent epithelial cell death, which is counteracted by the bacterial OspC3 effector. OspC3 interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization by depositing the conserved OspC3 X1-Y-X₂-D-X₃ motif at the putative catalytic pocket of caspase-4. Infection of guinea pigs with a Shigella ospC3-deficient mutant resulted in enhanced inflammatory cell death and associated symptoms, correlating with decreased bacterial burdens. Salmonella Typhimurium and enteropathogenic Escherichia coli infection also induced caspase-4-dependent epithelial death. These findings highlight the importance of caspase-4-dependent innate immune responses and demonstrate that Shigella delivers a caspase-4-specific inhibitor to delay epithelial cell death and promote infection.
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Taira
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Michinaga
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Sanada
authors.affiliation: Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ashida
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Akakura
authors.affiliation: Division of Ultrastructural Research, BioMedical Research Center, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9022 du Centre National de la Recherche Scientifique, Université de Strasbourg, 15, rue Rene Descartes, 67084 Strasbourg Cedex, France.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kawalec
authors.affiliation: Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9022 du Centre National de la Recherche Scientifique, Université de Strasbourg, 15, rue Rene Descartes, 67084 Strasbourg Cedex, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Reichhart
authors.affiliation: Picobiology Institute, Department of Life Science, Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigori, Akoh, Hyogo 678-1297, Japan.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Nippon Institute for Biological Science, 9-2221-1 Shinmachi, Ome, Tokyo 198-0024, Japan; Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan. Electronic address: sasakawa@ims.u-tokyo.ac.jp.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D004405:Dysentery, Bacillary / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D004847:Epithelial Cells / Q000382:microbiology*; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D055786:Gene Knockout Techniques; D006168:Guinea Pigs; D054884:Host-Pathogen Interactions; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D017422:Sequence Analysis, DNA; D012763:Shigella flexneri / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D037521:Virulence Factors; C093516:CASP4 protein, human; D053471:Caspases, Initiator