| Abstract: |
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–cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) 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. © 2024 by the authors. |
| Keywords: |
immunohistochemistry; adult; controlled study; protein expression; protein phosphorylation; carrier protein; unclassified drug; genetics; histopathology; nonhuman; comparative study; animal cell; mouse; phenotype; animal; metabolism; animals; mice; mice, knockout; animal tissue; gene expression; cell maturation; odor; epidermal growth factor receptor; protein; membrane proteins; mice, inbred c57bl; keratinocyte; physiology; c57bl mouse; rna; gene expression regulation; regulatory mechanism; carrier proteins; membrane protein; mitogen activated protein kinase 1; mitogen activated protein kinase 3; upregulation; g protein coupled receptor; knockout mouse; stable expression; olfactory receptor; gene ontology; olfactory receptor neurons; adaptation; tumor necrosis factor alpha converting enzyme; humans; human; article; rna sequencing; smelling; smell; olfactory epithelium; rnaseq; environmental change; adam17 (a disintegrin and metalloprotease 17); adam17 protein; turnover rate; irhom2 protein, mouse; olfactory mucosa; g-protein coupled receptor (gpcr); irhom2 (inactive rhomboid-like protein 2); olfactory epithelium (oe); olfactory receptor (or); olfactory sensory neuron (osn); rnascope in situ hybridization (ish); single-cell rnaseq analysis; receptors, odorant; inactive rhomboid like protein 1; inactive rhomboid like protein 2; protein s100a5; adam17 protein, mouse; olfactory receptor neuron
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