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

Weskamp, Gisela; Feederle, Regina; Swendemann, Steven; Blobel, Carl P.; Li, Daniel; Lichtenthaler, Stefan F.; Tüshaus, Johanna; Falck-Pedersen, Erik; McIlwain, David R.; Mak, Tak W.; Salmon, Jane E.; Maretzky, Thorsten

doi:10.1074/jbc.RA119.011136

Journal Article

DZNE-2020-01230

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

Weskamp, G. ; Tüshaus, J.DZNE* ; Li, D. ; Feederle, R.DZNE* ; Maretzky, T. ; Swendemann, S. ; Falck-Pedersen, E. ; McIlwain, D. R. ; Mak, T. W. ; Salmon, J. E. ; Lichtenthaler, S. F.DZNE* ; Blobel, C. P. (Corresponding author)

2020
American Soc. for Biochemistry and Molecular Biology8772 Bethesda, MD.

JBC papers in press 295(13), 4350 - 4358 (2020) [10.1074/jbc.RA119.011136]

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Please use a persistent id in citations: doi:10.1074/jbc.RA119.011136

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.

Keyword(s): ADAM17 Protein: genetics (MeSH) ; Animals (MeSH) ; Carrier Proteins: genetics (MeSH) ; Cell Membrane (MeSH) ; ErbB Receptors: genetics (MeSH) ; Fibroblasts: metabolism (MeSH) ; Gene Expression Regulation: genetics (MeSH) ; Humans (MeSH) ; Lipopolysaccharides: pharmacology (MeSH) ; Macrophages: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Mice (MeSH) ; Receptors, Interleukin-6: genetics (MeSH) ; Signal Transduction: genetics (MeSH) ; Tumor Necrosis Factor-alpha: genetics (MeSH)