Fungal adhesion protein guides community behaviors and autoinduction in a paracrine manner

Microbes live mostly in a social community rather than in a planktonic state. Such communities have complex spatiotemporal patterns that require intercellular communication to coordinate gene expression. Here, we demonstrate that Cryptococcus neoformans, a model eukaryotic pathogen, responds to an extracellular signal in constructing its colony morphology. The signal that directs this community behavior is not a molecule of low molecular weight like pheromones or quorum-sensing molecules but a secreted protein. Znf2, a master regulator of morphogenesis in Cryptococcus, is necessary and sufficient for the production of this signal protein. Cfl1, a prominent Znf2-downstream adhesion protein (adhesin), was identified to be responsible for the paracrine communication. Consistent with its role in communication, Cfl1 is highly induced during mating colony differentiation, and some of the Cfl1 proteins undergo shedding and are released from the cell wall. The released Cfl1 is enriched in the extracellular matrix and acts as an autoinduction signal to stimulate neighboring cells to phenocopy Cfl1-expressing cells via the filamentation-signaling pathway. We further demonstrate the importance of an unannotated and yet conserved domain in Cfl1’s signaling activity. Although adhesion proteins have long been considered to be mediators of microbial pathogenicity and the structural components of biofilms, our work presented here provides the direct evidence supporting the signaling activation by microbial adhesion/matrix proteins.