A novel Candida glabrata protein regulated by mating signaling pathway shapes inter-species interaction

During mixed-species invasive candidiasis - an emerging threat in healthcare - presence of Candida albicans is near-essential for host colonisation by C. glabrata. However, the molecular communication underlying such intriguing inter-species interaction is largely unexplored. Here, we show that C. glabrata secretes a unique small protein Yhi1 that induces hyphal growth in C. albicans, which is essential for host tissue invasion. Notably, this Yhi1-based inter-species interaction is specific to C. glabrata and C. albicans, when compared with other common species of Candida. Our structure-function analyses reveal a novel functional pentapeptide motif (AXVXH) required for the function of Yhi1. Interestingly, Yhi1 expression and efflux are regulated through the mating MAPK signalling pathway and the pheromone transporter CgSte6, respectively, in C. glabrata, despite its preferred asexual reproduction. Our findings shed light on how C. glabrata mating signalling pathway is repurposed to interact with C. albicans, and highlight the potential of Yhi1 as a biomarker and a template for a synthetic novel antifungal peptide.