Cross-Kingdom Control: Yeast Prion Protein Modulates Host Physiology in Drosophila

Clark, A. G.; Jiang, J. Y.; Chitale, M. D.; Cosgrove, E.; Van Elgort, A.; Jain, A. M.; Kelso, J. C.; Cui, X.; Yapici, N.; Lin, C.-c.

doi:10.64898/2026.08.26.747210

bioRxiv · 10.64898/2026.08.26.747210

Cross-Kingdom Control: Yeast Prion Protein Modulates Host Physiology in Drosophila

Clark, A. G.·Jiang, J. Y.·Chitale, M. D.·Cosgrove, E.·Van Elgort, A.·Jain, A. M.·Kelso, J. C.·Cui, X.·Yapici, N.·Lin, C.-c.

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Abstract

Prions, once mainly studied for their pathogenic roles, are now gaining recognition as adaptive elements in microbial physiology. Over one-third of wild yeast isolates harbor prion proteins, yet their impact on host-microbe interactions remains poorly characterized. Given the ecological dominance of yeasts in the Drosophila mycobiome, we leveraged the Drosophila melanogaster-Saccharomyces cerevisiae system to investigate how the mycobiome-derived prion, [MRPL10+], modulates host physiology. We show that flies exposed to [MRPL10+] yeast exhibit significantly enhanced cold tolerance and increased locomotor activity. This effect persists with heat-killed yeast and diluted culture, suggesting a stable, potent bioactive factor. Using the genetically diverse Drosophila Global Diversity Lines (GDL), we identified natural variation in responsiveness to [MRPL10+] yeast. Genome-wide association and functional RNAi screening revealed a gut-brain signaling axis involving genes critical for digestion, intercellular communication, transcription regulation, and neural transmission. Notably, serotonin and octopamine pathways were essential for [MRPL10+]-induced changes in cold tolerance and locomotion, implicating neuromodulatory circuits in prion-mediated microbial signaling. Our findings establish a mechanistic link between a fungal prion and host metabolic and neural adaptation. This work provides the first genetic dissection of a prion-mediated host-microbe interaction, laying the groundwork for investigating beneficial prions in complex microbial communities and highlighting a new dimension of the mycobiomes influence on animal physiology.

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Clark, A. G., Jiang, J. Y., Chitale, M. D., Cosgrove, E., Van Elgort, A., Jain, A. M., Kelso, J. C., Cui, X., Yapici, N., Lin, C.-c.. 2026-09-01. Cross-Kingdom Control: Yeast Prion Protein Modulates Host Physiology in Drosophila. https://doi.org/10.64898/2026.08.26.747210

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