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Cwh8 Moonlights as a Farnesyl Pyrophosphate Phosphatase and is Essential for Farnesol Biosynthesis in Candida albicans

ABSTRACT: In the opportunistic pathogen Candida albicans, hyphal growth and virulence factor expression are regulated by environmental and chemical cues. Farnesol is a secreted autoregulatory molecule that represses filamentation. It is derived from farnesyl pyrophosphate (FPP), an ergosterol biosynthesis pathway intermediate. Although Dpp1, Dpp2, and Dpp3 were proposed to synthesize farnesol, a mutant lacking all three had only a modest reduction in farnesol. To identify other farnesol biosynthesis genes, we employed transcription factor mutants that underproduced or overproduced farnesol in a screen and analyzed their transcriptomes. CWH8 was the only transcript correlated with farnesol production. Cwh8 is a lipid phosphatase known to recycle dolichyl pyrophosphate during glycosylation of cell wall proteins. The cwh8ΔΔ mutant had a >99% reduction in farnesol compared to the parent strain and was hyperfilamentous in embedded conditions. It had ~900-fold lower levels of farnesyl phosphate, the product of FPP dephosphorylation, suggesting Cwh8 acts directly on FPP. Complementation of the C. albicans cwh8ΔΔ mutant with CWH8 from C. albicans restored cell wall integrity and farnesol production. However, complementation with CWH8 from Clavispora lusitaniae, a species lacking farnesol signaling, restored cell wall integrity but failed to rescue farnesol production. This indicates that while Cwh8’s role in maintaining cell wall integrity is conserved, differences in substrate specificity or interactions with species-specific cofactors underlie its involvement in farnesol biosynthesis in C. albicans. Finally, fluconazole was fungicidal for cwh8ΔΔ rather than fungistatic. These studies demonstrate how an extracellular signaling system can arise and be co-opted to promote fungal fitness in complex environments.

ORGANISM(S): Candida albicans

PROVIDER: GSE289051 | GEO | 2025/08/26

REPOSITORIES: GEO

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Project description:Plasmodium falciparum is the etiological agent of human malaria, one of the most widespread diseases in tropical and subtropical world regions. One of the biggest problems in controlling the disease is the emergence of drug resistance, which leads to the need to discover new antimalarial compounds. One of the most promissory drugs purposed is fosmidomycin, an inhibitor of the biosynthesis of isoprene units by the methylerythritol 4-phosphate (MEP) pathway which in some cases failed in clinic studies. Once formed, isoprene units are condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (GGPP), which are necessary for heme O and A formation, ubiquinone, and dolichyl phosphate biosynthesis as well as for protein isoprenylation. Even though the natural substrates of polyprenyl transferases and syntheses are polyprenyl pyrophosphates, it was already demonstrated that isoprenoid alcohols (polyprenols) such as farnesol (FOH) and geranylgeraniol (GGOH) can rescue parasites from fosmidomycin. This study better investigated how this rescue phenomenon occurs by performing drug-rescue assays. By this, it was observed that phytol (POH), a 20-carbon plant isoprenoid, rescues parasites from the fosmidomycin effect, similarly to FOH or GGOH. Contrarily, neither dolichols nor nonaprenol rescue parasites from fosmidomycin. Considering this, here we characterized the transport of FOH, GGOH, and POH. Once incorporated, it was observed that these substances are phosphorylated, condensed into longer isoprenoid alcohols, and incorporated into proteins and dolichyl phosphates. Through proteomic and radiolabelling approaches, it was found that prenylated proteins are naturally attached to several isoprenoids including GGOH, dolichol, and POH if exogenously added. Furthermore, results suggest the presence of at least two promiscuous protein prenyltransferases in the parasite: one enzyme which can use FPP among other unidentified substrates and another enzyme that can use GGOH, POH, and dolichols among other substrates not identified here. Thus, was obtained further evidence for dolichols and other isoprenoid products attached to proteins. This study helps better understand apicoplast-targeting antimalarials mechanism of action as well as novel posttranslational modifications of proteins.

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Cwh8 Moonlights as a Farnesyl Pyrophosphate Phosphatase and is Essential for Farnesol Biosynthesis in Candida albicans

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