The iRhom homology domain is indispensable for ADAM17-mediated TNF alpha and EGF receptor ligand release

0544132 - ÚMG 2022 RIV CH eng J - Journal Article
Dusterhoft, S. - Kahveci-Tuerkoez, S. - Wozniak, J. - Seifert, A. - Kašpárek, Petr - Ohm, H. - Liu, S. - Kopkanová, Jana - Lokau, J. - Garbers, C. - Preisinger, C. - Sedláček, Radislav - Freeman, M. - Ludwig, A.
The iRhom homology domain is indispensable for ADAM17-mediated TNF alpha and EGF receptor ligand release.
Cellular and Molecular Life Sciences. Roč. 78, č. 11 (2021), s. 5015-5040. ISSN 1420-682X. E-ISSN 1420-9071
Institutional support: RVO:68378050
Keywords : iRhom * adam17 * Ectodomain shedding * tnf * Growth factors * iRhom homology domain
OECD category: Biochemistry and molecular biology
Impact factor: 9.234, year: 2021
Method of publishing: Open access
https://link.springer.com/article/10.1007/s00018-021-03845-3

Membrane-tethered signalling proteins such as TNF alpha and many EGF receptor ligands undergo shedding by the metalloproteinase ADAM17 to get released. The pseudoproteases iRhom1 and iRhom2 are important for the transport, maturation and activity of ADAM17. Yet, the structural and functional requirements to promote the transport of the iRhom-ADAM17 complex have not yet been thoroughly investigated. Utilising in silico and in vitro methods, we here map the conserved iRhom homology domain (IRHD) and provide first insights into its structure and function. By focusing on iRhom2, we identified different structural and functional factors within the IRHD. We found that the structural integrity of the IRHD is a key factor for ADAM17 binding. In addition, we identified a highly conserved motif within an unstructured region of the IRHD, that, when mutated, restricts the transport of the iRhom-ADAM17 complex through the secretory pathway in in vitro, ex vivo and in vivo systems and also increases the half-life of iRhom2 and ADAM17. Furthermore, the disruption of this IRHD motif was also reflected by changes in the yet undescribed interaction profile of iRhom2 with proteins involved in intracellular vesicle transport. Overall, we provide the first insights into the forward trafficking of iRhoms which is critical for TNF alpha and EGF receptor signalling.
Permanent Link: http://hdl.handle.net/11104/0321178