Glucosamine stimulates pheromone-independent dimorphic transition in Cryptococcus neoformans by promoting Crz1 nuclear translocation

Abstract

Morphotype switch is a cellular response to external and internal cues. The Cryptococcus neoformans species complex can undergo morphological transitions between the yeast and the hypha form, and such morphological changes profoundly affect cryptococcal interaction with various hosts. Filamentation in Cryptococcus was historically considered a mating response towards pheromone. Recent studies indicate the existence of pheromone-independent signaling pathways but their identity or the effectors remain unknown. Here, we demonstrated that glucosamine stimulated the C. neoformans species complex to undergo self-filamentation. Glucosamine-stimulated filamentation was independent of the key components of the pheromone pathway, which is distinct from pheromone-elicited filamentation. Glucosamine stimulated self-filamentation in H99, a highly virulent serotype A clinical isolate and a widely used reference strain. Through a genetic screen of the deletion sets made in the H99 background, we found that Crz1, a transcription factor downstream of calcineurin, was essential for glucosamine-stimulated filamentation despite its dispensability for pheromone-mediated filamentation. Glucosamine promoted Crz1 translocation from the cytoplasm to the nucleus. Interestingly, multiple components of the high osmolality glycerol response (HOG) pathway, consisting of the phosphorelay system and some of the Hog1 MAPK module, acted as repressors of glucosamine-elicited filamentation through their calcineurin-opposing effect on Crz1’s nuclear translocation. Surprisingly, glucosamine-stimulated filamentation did not require Hog1 itself and was distinct from the conventional general stress response. The results demonstrate that Cryptococcus can resort to multiple genetic pathways for morphological transition in response to different stimuli. Given that the filamentous form attenuates cryptococcal virulence and is immune-stimulatory in mammalian models, the findings suggest that morphogenesis is a fertile ground for future investigation into novel means to compromise cryptococcal pathogenesis.

PAS Domain Protein Pas3 Interacts with the Chromatin Modifier Bre1 in Regulating Cryptococcal Morphogenesis

“…To this end, we transformed the inducible promoter-driven and mCherry-tagged ZNF2 gene into the pas3 Δ mutant. As we have shown previously ( 40 ), Znf2 is localized to the nucleus ( Fig. 3E ).…”

Unisexual reproduction promotes competition for mating partners in the global human fungal pathogenCryptococcus deneoformans

“…These expression analyses suggest that pheromone response pathway activation per se is not sufficient to explain the ability to undergo unisexual reproduction and its association with competition for mating partners. It was previously shown that the cell fusion protein Prm1 is not required for unisexual reproduction [26], and certain environmental factors, such as copper and glucosamine, can induce hyphal growth independently of the pheromone response pathway [23, 24]. In a recent study on the quorum sensing peptide Qsp1, deletion of pheromone and pheromone receptor genes had little impact on hyphal growth during unisexual reproduction [25], further indicating the polygenic nature of unisexual reproduction.…”

N-Acetylglucosamine Regulates Morphogenesis and Virulence Pathways in Fungi

“…In contrast, GlcNAc has been shown to inhibit hyphal growth in Candida tropicalis, although GlcNAc was still able to induce the White to Opaque switch [102,103], and it was not able to induce true hyphae in Candida dubliniensis [104]. It is also interesting that glucosamine, but not GlcNAc, can stimulate filamentous growth of Cryptococcus neoformans [105].…”