4-hydroxy-5-methyl-3(2H)-furanone mediates widespread interkingdom communications between fungi and prokaryotes

Fungal-prokaryotic interactions are widespread in natural and host-associated habitats. These interactions are believed to play crucial roles in ecosystem functioning and health. However, the cell-cell interaction mechanisms between these two types of microorganisms remain largely unknown.

We demonstrate that fungi Saccharomyces cerevisiae and Cryptococcus neoformans secrete 4-hydroxy-5-methyl-3(2H)-furanone (MHF), which chemoattracts Pseudomonas aeruginosa via the dCache_1-type ligand-binding domains (LBDs) of the chemoreceptors PctA and TlpQ. We also solved high-resolution structures of PctA-LBD and TlpQ-LBD in complex with MHF. Bioinformatic analyses suggest that the MHF synthase Cff1p is widespread among fungi, and functionally distinct dCache_1-containing transmembrane receptors capable of sensing MHF are prevalent across diverse bacteria and archaea. Functional assays confirm MHF binding enhances enzymatic activities of representative dCache_1-type LBD-containing receptors. Finally, communication network analysis suggests that MHF-mediated fungal-prokaryotic interactions are widespread between members of the fungal phyla Ascomycota and Basidiomycota and the bacterial phyla Pseudomonadota and Bacillota.

These findings identify MHF as a broadly utilised fungal signal mediating extensive interkingdom communications between fungi and prokaryotes, highlighting its potential role in shaping microbial community dynamics.