A small Candida glabrata protein promotes hyphal growth in C. albicans during mixed-species invasive candidiasis

During mixed-species invasive candidiasis-an emerging threat in healthcare-the presence of Candida albicans is nearly essential for host invasion by C. glabrata. However, the molecular communication underlying such intriguing inter-species fungal interactions is largely unexplored. Here, we show that C. glabrata secretes a unique small protein, Yhi1-encoded by a likely de novo gene-which induces hyphal growth via Tsa1 in C. albicans. Notably, this Yhi1-based inter-species interaction is specific to C. glabrata and C. albicans compared with other common species of Candida. Our structure-function analyses reveal a new functional pentapeptide motif (AXVXH) required for the function of Yhi1. Interestingly, Yhi1 expression and efflux are regulated through the mating mitogen-activated protein kinase (MAPK) signaling pathway and the pheromone transporter CgSte6, respectively, in C. glabrata. Given its preference for asexual reproduction, our findings shed light on how C. glabrata has repurposed the mating signaling pathway to interact with C. albicans.