Authors: Janet Chih-chun Lin 1; Maushmi D. Chitale 1; Jessica Y. Jiang 1; Elissa J. Cosgrove 1; Alexandria C. Van Elgort 2; Asha M. Jain 1; Julia C. Kelso 1; Danial F. Jarosz 2; Andrew G. Clark 1
Affiliations: 1) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY; 2) Department of Chemical and Systems Biology, Stanford University, Stanford, CA
Keywords: Genetic interactions
Prions, misfolded proteins best known for causing mad cow disease, can help yeasts survive harsh environmental conditions. The prion-directed beneficial traits can also be passed down to their offspring for >100 generations. In addition, more than one-third of wild yeast isolates are found to harbor various kinds of prion proteins. Forming prion proteins seems to be a common strategy for microbes to endure physiological challenges. However, whether and how these yeast prions play a role in host-microbe interaction is entirely unknown. Fruit flies routinely encounter yeasts in the wild and the lab. Yeasts are an essential member of the fly mycobiome. They not only serve as a protein source, but yeasts also provide significant signaling cues regulating fly physiology, reproduction, and behavior. Here we use Drosophila melanogaster and Saccharomycescerevisiae as a model to investigate the mechanism by which mycobiome-derived prions impact host health. After testing a battery of prion proteins, we found yeasts with the prion protein [MRPL10+] significantly promote cold tolerance in flies. We also discovered a wide range of cold tolerance levels across global diversity lines (GDLs), a collection of fly lines with different genetic backgrounds. By harnessing the power of large-scale GDL screening, GWAS, functional genomics, and RNAi screening, we identified a list of candidate fly genes functionally crucial in responding to yeast-derived prion protein [MRPL10+]. Following up on several candidate genes, we uncovered the neuronal cause of the cold tolerance phenotype in flies. Our results reveal the novel link between fungal prion proteins and host physiology. This appears to be the first systematic analysis of the genetic interaction of fungal prions in the host. Our approach will facilitate the discovery of beneficial prions in microbes and provide mechanistic insight into the mycobiome field.