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

S. Düsterhöft, S. Kahveci-Türköz, J. Wozniak, A. Seifert, P. Kasparek, H. Ohm, S. Liu, J. Kopkanova, J. Lokau, C. Garbers, C. Preisinger, R. Sedlacek, M. Freeman, A. Ludwig

. 2021 ; 78 (11) : 5015-5040. [pub] 20210505

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc21025644

Grantová podpora
101035/Z/13/Z Wellcome Trust - United Kingdom
IZKF Aachen A-1-5 Medizinische Fakultät, RWTH Aachen University
125440785 - SFB 877/projects A10 and A14 Deutsche Forschungsgemeinschaft
#691903-06/19 Medizinische Fakultät, RWTH Aachen University
DU 1582/1-1 Deutsche Forschungsgemeinschaft
StUpPD_299-18 Medizinische Fakultät, RWTH Aachen University
Wellcome Trust - United Kingdom
Lu869/8-1 Deutsche Forschungsgemeinschaft

Membrane-tethered signalling proteins such as TNFα 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 TNFα and EGF receptor signalling.

Citace poskytuje Crossref.org

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$a Membrane-tethered signalling proteins such as TNFα 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 TNFα and EGF receptor signalling.
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