Abstract
In the fungal pathogen Cryptococcus neoformans, the switch from yeast to hypha is an important morphological process preceding the meiotic events during sexual development. Morphotype is also known to be associated with cryptococcal virulence potential. Previous studies identified the regulator Znf2 as a key decision maker for hypha formation and as an anti-virulence factor. By a forward genetic screen, we discovered that a long non-coding RNA (lncRNA) RZE1 functions upstream of ZNF2 in regulating yeast-to-hypha transition. We demonstrate that RZE1 functions primarily in cis and less effectively in trans. Interestingly, RZE1’s function is restricted to its native nucleus. Accordingly, RZE1 does not appear to directly affect Znf2 translation or the subcellular localization of Znf2 protein. Transcriptome analysis indicates that the loss of RZE1 reduces the transcript level of ZNF2 and Znf2’s prominent downstream targets. In addition, microscopic examination using single molecule fluorescent in situ hybridization (smFISH) indicates that the loss of RZE1 increases the ratio of ZNF2 transcripts in the nucleus versus those in the cytoplasm. Taken together, this lncRNA controls Cryptococcus yeast-to-hypha transition through regulating the key morphogenesis regulator Znf2. This is the first functional characterization of a lncRNA in a human fungal pathogen. Given the potential large number of lncRNAs in the genomes of Cryptococcus and other fungal pathogens, the findings implicate lncRNAs as an additional layer of genetic regulation during fungal development that may well contribute to the complexity in these “simple” eukaryotes.
Highlights
We further discovered that RZE1 regulates the transcription and transcript export of ZNF2, which encodes the key morphogenesis transcription factor
In many human fungal pathogens, the morphological transition from yeast to hypha plays a central role in pathogenesis [1, 2], as demonstrated in the ascomycetes Candida albicans, Penicillium marneffei, Histoplasma capsulatum, Coccidioides immitis, and Paracoccidiodides brasiliensis [3,4,5,6]
Mat2 is essential for pheromone sensing and response, which leads to the cell fusion event
Summary
In many human fungal pathogens, the morphological transition from yeast to hypha plays a central role in pathogenesis [1, 2], as demonstrated in the ascomycetes Candida albicans, Penicillium marneffei, Histoplasma capsulatum, Coccidioides immitis, and Paracoccidiodides brasiliensis [3,4,5,6]. Znf is activated by the pheromone MAPK pathway controlled by the HMG domain transcription factor Mat2 [12,13,14,15] (Fig 1A). Znf governs hypha generation and it is dispensable for the early mating events like cell fusion [12, 17] (Fig 1A). Under non-mating inducing conditions, Znf could be activated by the matri-cellular signal protein Cfl through a positive feedback regulation [18, 19]. It is unknown whether other host or environmental factors can regulate Znf activity
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