title: Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17.
abstract: The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors. Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF, a cytokine that is critical in the innate immune response and promotes programmed cell death but can also promote sepsis. Catalytically inactive members of the rhomboid family of proteases, iRhom1 and iRhom2, mediate the intracellular transport and maturation of ADAM17. Using a genetic screen, we found that the presence of either iRhom1 or iRhom2 lacking part of their extended amino-terminal cytoplasmic domain (herein referred to as ΔN) increases ADAM17 activity, TNFR shedding, and resistance to TNF-induced cell death in fibrosarcoma cells. Inhibitors of ADAM17, but not of other ADAM family members, prevented the effects of iRhom-ΔN expression. iRhom1 and iRhom2 were functionally redundant, suggesting a conserved role for the iRhom amino termini. Cells from patients with a dominantly inherited cancer susceptibility syndrome called tylosis with esophageal cancer (TOC) have amino-terminal mutations in iRhom2. Keratinocytes from TOC patients exhibited increased TNFR1 shedding compared with cells from healthy donors. Our results explain how loss of the amino terminus in iRhom1 and iRhom2 impairs TNF signaling, despite enhancing ADAM17 activity, and may explain how mutations in the amino-terminal region contribute to the cancer predisposition syndrome TOC.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Sathish K
authors.initials: SK
authors.lastname: Maney
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: McIlwain
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Polz
authors.affiliation: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, Essen 45147, Germany.
authors.forename: Aleksandra A
authors.initials: AA
authors.lastname: Pandyra
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Balamurugan
authors.initials: B
authors.lastname: Sundaram
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Dorit
authors.initials: D
authors.lastname: Wolff
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Ohishi
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maretzky
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brooke
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Evers
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Ananda A Jaguva
authors.initials: AA
authors.lastname: Vasudevan
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Aghaeepour
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Münk
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Campell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Departments of Medicine and of Physiology, Biophysics and Systems Biology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.affiliation: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, Essen 45147, Germany.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. philipp.lang@med.uni-duesseldorf.de.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human