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Sci Signal. 2015 Nov 3;8(401):ra109. doi: 10.1126/scisignal.aac5356.

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

Author information

1
Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
2
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.
3
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, Essen 45147, Germany.
4
Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
5
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
6
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.
7
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
8
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
9
Campell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada.
10
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.
11
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.

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.

PMID:
26535007
DOI:
10.1126/scisignal.aac5356
[Indexed for MEDLINE]

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