title: iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS.
abstract: Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.
authors.affiliation: Campell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network (UHN), 620 University Avenue, Toronto, Ontario M5G 2C1, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: McIlwain
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maretzky
authors.forename: Koichi
authors.initials: K
authors.lastname: Hamada
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Ohishi
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Maney
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.forename: Aditya
authors.initials: A
authors.lastname: Murthy
authors.forename: Gordon
authors.initials: G
authors.lastname: Duncan
authors.forename: Haifeng C
authors.initials: HC
authors.lastname: Xu
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Annick
authors.initials: A
authors.lastname: Itie-Youten
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D017353:Gene Deletion; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology / Q000502:physiology; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D021381:Protein Transport; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C569468:iRhom2 protein, mouse; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse