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ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1).

TitleADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1).
Publication TypeJournal Article
Year of Publication2020
AuthorsWeskamp G, Tüshaus J, Li D, Feederle R, Maretzky T, Swendemann S, Falck-Pedersen E, McIlwain DR, Mak TW, Salmon JE, Lichtenthaler SF, Blobel CP
JournalJ Biol Chem
Volume295
Issue13
Pagination4350-4358
Date Published2020 03 27
ISSN1083-351X
Abstract

The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) is a key regulator of tumor necrosis factor α (TNFα), interleukin 6 receptor (IL-6R), and epidermal growth factor receptor (EGFR) signaling. ADAM17 maturation and function depend on the seven-membrane-spanning inactive rhomboid-like proteins 1 and 2 (iRhom1/2 or Rhbdf1/2). Most studies to date have focused on overexpressed iRhom1 and -2, so only little is known about the properties of the endogenous proteins. Here, we show that endogenous iRhom1 and -2 can be cell surface-biotinylated on mouse embryonic fibroblasts (mEFs), revealing that endogenous iRhom1 and -2 proteins are present on the cell surface and that iRhom2 also is present on the surface of lipopolysaccharide-stimulated primary bone marrow-derived macrophages. Interestingly, very little, if any, iRhom2 was detectable in mEFs or bone marrow-derived macrophages lacking ADAM17, suggesting that iRhom2 is stabilized by ADAM17. By contrast, the levels of iRhom1 were slightly increased in the absence of ADAM17 in mEFs, indicating that its stability does not depend on ADAM17. These findings support a model in which iRhom2 and ADAM17 are obligate binding partners and indicate that iRhom2 stability requires the presence of ADAM17, whereas iRhom1 is stable in the absence of ADAM17.

DOI10.1074/jbc.RA119.011136
Alternate JournalJ Biol Chem
PubMed ID32060096
PubMed Central IDPMC7105298
Grant ListR01 GM064750 / GM / NIGMS NIH HHS / United States
R35 GM134907 / GM / NIGMS NIH HHS / United States

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