{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T06:11:08Z","timestamp":1768889468683,"version":"3.49.0"},"reference-count":60,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T00:00:00Z","timestamp":1717113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R35 GM134907"],"award-info":[{"award-number":["R35 GM134907"]}]},{"name":"NIH","award":["R01 DC020353"],"award-info":[{"award-number":["R01 DC020353"]}]},{"name":"NIH","award":["DC021585"],"award-info":[{"award-number":["DC021585"]}]},{"name":"NIH","award":["T32GM007739"],"award-info":[{"award-number":["T32GM007739"]}]},{"name":"NIH","award":["T32AR071302"],"award-info":[{"award-number":["T32AR071302"]}]},{"name":"NIH","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell\u2013cell interactions by mediating the release of membrane proteins such as TNF\u03b1 (Tumor necrosis factor \u03b1) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. iRhom2-\/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-\/- OE, OSNs expressing ORs that are enriched in iRhom2-\/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2\/ADAM17, we investigated if ORs could activate iRhom2\/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1\/2 phosphorylation, likely via an iRhom2\/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2\/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.<\/jats:p>","DOI":"10.3390\/ijms25116079","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T06:35:32Z","timestamp":1717137332000},"page":"6079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9585-9234","authenticated-orcid":false,"given":"Stephanie A.","family":"Azzopardi","sequence":"first","affiliation":[{"name":"Weill Cornell Medicine\/Rockefeller University\/Memorial Sloan-Kettering Cancer Center, Tri-Institutional MD-PhD Program, New York, NY 10021, USA"},{"name":"Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, NY 10021, USA"},{"name":"Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsiu-Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastien","family":"Monette","sequence":"additional","affiliation":[{"name":"Tri-Institutional Laboratory of Comparative Pathology, Hospital for Special Surgery, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariana I.","family":"Rabinowitsch","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine\/Rockefeller University\/Memorial Sloan-Kettering Cancer Center, Tri-Institutional MD-PhD Program, New York, NY 10021, USA"},{"name":"Department of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9113-7122","authenticated-orcid":false,"given":"Jane E.","family":"Salmon","sequence":"additional","affiliation":[{"name":"Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA"},{"name":"Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8850-2608","authenticated-orcid":false,"given":"Hiroaki","family":"Matsunami","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"},{"name":"Department of Neurobiology, Duke Institute for Brain Sciences, Duke University, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-3137","authenticated-orcid":false,"given":"Carl P.","family":"Blobel","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine\/Rockefeller University\/Memorial Sloan-Kettering Cancer Center, Tri-Institutional MD-PhD Program, New York, NY 10021, USA"},{"name":"Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, NY 10021, USA"},{"name":"Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA"},{"name":"Department of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USA"},{"name":"Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1126\/science.1214448","article-title":"iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS","volume":"335","author":"McIlwain","year":"2012","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1126\/science.1214400","article-title":"Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE","volume":"335","author":"Adrain","year":"2012","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5769","DOI":"10.1182\/blood-2012-03-417949","article-title":"iRhom2 is required for the secretion of mouse 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