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Updated: Dec 28, 2025
Rat Model of Adhesive Capsulitis of the Shoulder
Published on: September 28, 2018
ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1)
Gisela Weskamp1, Johanna Tüshaus2, Daniel Li1
1Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021.
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.
Insights
Endogenous inactive rhomboid-like proteins 1 and 2 (iRhom1/2) are cell surface proteins crucial for ADAM17 regulation. iRhom2 stability depends on ADAM17, while iRhom1 is stable independently.
Area of Science:
- Cell biology
- Molecular and cellular biology
- Biochemistry
Background:
- ADAM17 (a disintegrin and metalloprotease 17) is essential for regulating key signaling pathways, including TNFα, IL-6R, and EGFR.
- ADAM17's function and maturation rely on inactive rhomboid-like proteins 1 and 2 (iRhom1/2).
- Previous research primarily investigated overexpressed iRhom1/2, leaving the properties of endogenous proteins largely unknown.
Purpose of the Study:
- To investigate the cellular localization and properties of endogenous iRhom1 and iRhom2.
- To determine the relationship between ADAM17 and the stability of endogenous iRhom1 and iRhom2.
Main Methods:
- Cell surface biotinylation of mouse embryonic fibroblasts (mEFs) and primary bone marrow-derived macrophages.
- Analysis of iRhom1 and iRhom2 protein levels in wild-type and ADAM17-deficient cells.
Main Results:
- Endogenous iRhom1 and iRhom2 were detected on the cell surface of mEFs.
- iRhom2 was also found on the surface of lipopolysaccharide-stimulated macrophages.
- iRhom2 levels were significantly reduced in cells lacking ADAM17, suggesting stabilization by ADAM17.
- iRhom1 levels slightly increased in the absence of ADAM17, indicating its stability is independent of ADAM17.
Conclusions:
- Endogenous iRhom1 and iRhom2 are present on the cell surface.
- iRhom2 and ADAM17 appear to be obligate binding partners, with iRhom2 stability requiring ADAM17.
- iRhom1 stability is independent of ADAM17.
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