Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17

Sathish K Maney; David R McIlwain; Robin Polz; Aleksandra A Pandyra; Balamurugan Sundaram; Dorit Wolff; Kazuhito Ohishi; Thorsten Maretzky; Matthew A Brooke; Astrid Evers; Ananda A Jaguva Vasudevan; Nima Aghaeepour; Jürgen Scheller; Carsten Münk; Dieter Häussinger; Tak W Mak; Garry P Nolan; David P Kelsell; Carl P Blobel; Karl S Lang; Philipp A Lang

doi:10.1126/scisignal.aac5356

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Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17

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Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17

Sathish K Maney, David R McIlwain, Robin Polz, Aleksandra A Pandyra, Balamurugan Sundaram, Dorit Wolff, Kazuhito Ohishi, Thorsten Maretzky, Matthew A Brooke, Astrid Evers, …

Science signaling, Vol.8(401), pp.ra109-ra109

11/03/2015

DOI: 10.1126/scisignal.aac5356

PMCID: PMC7202466

PMID: 26535007

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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.

ADAM17 Protein

Protein Structure, Tertiary

Receptors, Tumor Necrosis Factor - metabolism

Genetic Predisposition to Disease

Keratoderma, Palmoplantar - genetics

Humans

Fibrosarcoma - metabolism

Neoplasm Proteins - metabolism

Esophageal Neoplasms - pathology

ADAM Proteins - metabolism

Fibrosarcoma - genetics

Fibrosarcoma - pathology

Esophageal Neoplasms - genetics

Keratoderma, Palmoplantar - metabolism

Keratoderma, Palmoplantar - pathology

Esophageal Neoplasms - metabolism

Cell Line, Tumor

Mutation

ADAM Proteins - genetics

Neoplasm Proteins - genetics

Receptors, Tumor Necrosis Factor - genetics

Details

Title: Subtitle: Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17
Creators: Sathish K Maney - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
David R McIlwain - 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
Robin Polz - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Aleksandra A Pandyra - Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, Essen 45147, Germany
Balamurugan Sundaram - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Dorit Wolff - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Kazuhito Ohishi - Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Thorsten Maretzky - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
Matthew A Brooke - 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
Astrid Evers - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
Ananda A Jaguva Vasudevan - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Nima Aghaeepour - Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
Jürgen Scheller - Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Carsten Münk - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Dieter Häussinger - Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Tak W Mak - Campell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada
Garry P Nolan - Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
David P Kelsell - 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
Carl P Blobel - 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
Karl S Lang - Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, Essen 45147, Germany
Philipp A Lang - 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
Resource Type: Journal article
Publication Details: Science signaling, Vol.8(401), pp.ra109-ra109
DOI: 10.1126/scisignal.aac5356
PMID: 26535007
PMCID: PMC7202466
NLM abbreviation: Sci Signal
ISSN: 1945-0877
eISSN: 1937-9145
Grant note: MR/L010402/1 / Medical Research Council U19 AI100627 / NIAID NIH HHS 41000411217 / PHS HHS R01 CA184968 / NCI NIH HHS R01CA184968 / NCI NIH HHS C7570/A19107 / Cancer Research UK R01 GM064750 / NIGMS NIH HHS R33 CA183654 / NCI NIH HHS 1 R33 CA183654 / NCI NIH HHS N01-HV-00242 / NHLBI NIH HHS 201210MFE-289576-150035 / CIHR U19 AI057229 / NIAID NIH HHS 7500108142 / PHS HHS 5R01AI07372405 / NIAID NIH HHS U54 CA149145 / NCI NIH HHS HHSF223201210194C / PHS HHS U54CA149145 / NCI NIH HHS GM64750 / NIGMS NIH HHS R33 CA183692 / NCI NIH HHS 1U19AI100627 / NIAID NIH HHS
Language: English
Date published: 11/03/2015
Academic Unit: Internal Medicine
Record Identifier: 9984094323202771

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