| First Author | Düsterhöft S | Year | 2021 |
| Journal | Cell Mol Life Sci | Volume | 78 |
| Issue | 11 | Pages | 5015-5040 |
| PubMed ID | 33950315 | Mgi Jnum | J:310482 |
| Mgi Id | MGI:6762779 | Doi | 10.1007/s00018-021-03845-3 |
| Citation | Dusterhoft S, et al. (2021) The iRhom homology domain is indispensable for ADAM17-mediated TNFalpha and EGF receptor ligand release. Cell Mol Life Sci 78(11):5015-5040 |
| abstractText | Membrane-tethered signalling proteins such as TNFalpha 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 TNFalpha and EGF receptor signalling. |
