title: Shigella Effector OspB Activates mTORC1 in a Manner That Depends on IQGAP1 and Promotes Cell Proliferation.
abstract: The intracellular bacterial pathogen Shigella infects and spreads through the human intestinal epithelium. Effector proteins delivered by Shigella into cells promote infection by modulating diverse host functions. We demonstrate that the effector protein OspB interacts directly with the scaffolding protein IQGAP1, and that the absence of either OspB or IQGAP1 during infection leads to larger areas of S. flexneri spread through cell monolayers. We show that the effect on the area of bacterial spread is due to OspB triggering increased cell proliferation at the periphery of infected foci, thereby replacing some of the cells that die within infected foci and restricting the area of bacterial spread. We demonstrate that OspB enhancement of cell proliferation results from activation of mTORC1, a master regulator of cell growth, and is blocked by the mTORC1-specific inhibitor rapamycin. OspB activation of mTORC1, and its effects on cell proliferation and bacterial spread, depends on IQGAP1. Our results identify OspB as a regulator of mTORC1 and mTORC1-dependent cell proliferation early during S. flexneri infection and establish a role for IQGAP1 in mTORC1 signaling. They also raise the possibility that IQGAP1 serves as a scaffold for the assembly of an OspB-mTORC1 signaling complex.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, United States of America; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Bobby Brooke
authors.initials: BB
authors.lastname: Herrera
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, United States of America; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Eshleman
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bloom
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Sacks
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, United States of America; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Marcia B
authors.initials: MB
authors.lastname: Goldberg
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D004405:Dysentery, Bacillary / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D034741:RNA, Small Interfering; D012763:Shigella flexneri / Q000472:pathogenicity*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
chemical_list: D001425:Bacterial Outer Membrane Proteins; C101203:IQ motif containing GTPase activating protein 1; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases