A co-evolved peptide-GPCR system senses host entry to drive fungal infection
Abstract
A successful infection requires pathogens to recognize the specific host environment in order to reprogram their physiology accordingly. 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 Ustilago maydis 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 ‘hidden’ 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.
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BibTeX
@article{mendozarojas2026coevolved,
title = {{A co-evolved peptide-GPCR system senses host entry to drive fungal infection}},
author = {Gabriel Mendoza-Rojas and Philip Nakonz and Min Lu and Nora Marie Kühne and Johannes Postma and Naomi Shtakser and Max Heinen and Manav Patel and Orlando Arguello-Miranda and Kai Heimel and Sonja Billerbeck and Florian Altegoer},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78428-6},
url = {https://www.nature.com/articles/s41467-026-78428-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A co-evolved peptide-GPCR system senses host entry to drive fungal infection
AU - Gabriel Mendoza-Rojas
AU - Philip Nakonz
AU - Min Lu
AU - Nora Marie Kühne
AU - Johannes Postma
AU - Naomi Shtakser
AU - Max Heinen
AU - Manav Patel
AU - Orlando Arguello-Miranda
AU - Kai Heimel
AU - Sonja Billerbeck
AU - Florian Altegoer
PY - 2026
DA - 2026/10/09
JO - Nature Communications
DO - 10.1038/s41467-026-78428-6
UR - https://www.nature.com/articles/s41467-026-78428-6
AB - A successful infection requires pathogens to recognize the specific host environment in order to reprogram their physiology accordingly. 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 Ustilago maydis 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 ‘hidden’ 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.
SN - 2041-1723
ER -