Saccharomyces cerevisiae Requires CFF1 to Produce 4-hydroxy-5-methylfuran-3(2H)-one, a Mimic of the Bacterial Quorum-Sensing Autoinducer AI-2

Abstract

Quorum sensing is a process of cell-to-cell communication that bacteria use to orchestrate collective behaviors. Quorum sensing depends on the production, release, and detection of extracellular signal molecules called autoinducers (AIs) that accumulate with increasing cell density. While most AIs are species-specific, the AI called AI-2 is produced and detected by diverse bacterial species and it mediates inter-species communication. We recently reported that mammalian cells produce an AI-2 mimic that can be detected by bacteria through the AI-2 receptor, LuxP, potentially expanding the role of the AI-2 system to inter-domain communication. Here, we describe a second molecule capable of inter-domain signaling through LuxP, 4-hydroxy-5-methylfuran-3(2H)-one (MHF) that is produced by the yeast Saccharomyces cerevisiae. Screening the S. cerevisiae deletion collection revealed Cff1p, a protein with no known role, to be required for MHF production. Cff1p is proposed to be an enzyme, possibly an epimerase or isomerase, and substitution at the putative catalytic residue eliminated MHF production in S. cerevisiae. Sequence analysis uncovered Cff1p homologs in many species, primarily bacterial and fungal, but also viral, archaeal, and higher eukaryotic. Cff1p homologs from organisms from all domains can complement a S. cerevisiae cff1{Delta} mutant and restore MHF production. In all test cases, the identified catalytic residue is conserved and required for MHF to be produced. These findings increase the scope of possibilities for inter-domain interactions via AI-2 and AI-2 mimics, highlighting the breadth of molecules and organisms that could participate in quorum sensing. ImportanceQuorum sensing is a cell-to-cell communication process that bacteria use to monitor local population density. Quorum sensing relies on extracellular signal molecules called autoinducers (AIs). One AI, called AI-2, is broadly made by bacteria and used for inter-species communication. Here, we describe a eukaryotic AI-2 mimic, 5-methylfuran-3(2H)-one, (MHF), that is made by the yeast Saccharomyces cerevisiae, and we identify the Cff1p protein as essential for MHF production. Hundreds of viral, archaeal, bacterial, and eukaryotic organisms possess Cff1p homologs. This finding, combined with our results showing that homologs from all domains can replace S. cerevisiae Cff1p, suggests that like AI-2, MHF is widely produced. Our results expand the breadth of organisms that may participate in quorum-sensing-mediated interactions.