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One major way in which eukaryotic cells sense their surroundings is via G-Protein Coupled Receptors (GPCRs), which share a seven-transmembrane architecture and G-protein-mediated downstream signaling. While mammalian GPCRs are well-characterized and represent important drug targets, their fungal counterparts remain poorly understood. Here we uncover a GPCR-based mechanism that allows the corn pathogen\n                    <jats:italic>Ustilago maydis<\/jats:italic>\n                    to sense whether it has entered plant tissue. During infection, the fungus secretes the protein Pit2, which is cleaved by host apoplastic cysteine proteases, releasing a peptide ligand \u2018hidden\u2019 within the protein core. This ligand activates the fungal GPCR Gpe1, thus promoting fungal proliferation after initial host penetration. We elucidate the crystal structure of Pit2 and model the complex formed by Gpe1 and the Pit2-derived peptide. Structure-guided mutational analysis supports that disrupting this interaction reduces fungal virulence. The Gpe1\/Pit2 system is conserved in related fungal species, with co-evolutionary signatures apparently preserving receptor-ligand specificity. Furthermore, this system shows mechanistic similarities to mammalian receptors, suggesting an evolutionary link between fungal and mammalian GPCRs.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-78428-6","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:34:35Z","timestamp":1791556475000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A co-evolved peptide-GPCR system senses host entry to drive fungal infection"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9039-8320","authenticated-orcid":false,"given":"Gabriel","family":"Mendoza-Rojas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3166-9671","authenticated-orcid":false,"given":"Philip","family":"Nakonz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora Marie","family":"K\u00fchne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0565-4487","authenticated-orcid":false,"given":"Johannes","family":"Postma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Shtakser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2041-5011","authenticated-orcid":false,"given":"Max","family":"Heinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9064-443X","authenticated-orcid":false,"given":"Manav","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0579-4650","authenticated-orcid":false,"given":"Orlando","family":"Arguello-Miranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Heimel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Billerbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6012-9047","authenticated-orcid":false,"given":"Florian","family":"Altegoer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"78428_CR1","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1161\/CIRCRESAHA.124.323067","volume":"135","author":"S Liu","year":"2024","unstructured":"Liu, S., Anderson, P. 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