A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling

Abstract

The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-tohyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases.

Novel regulators of nitric oxide signaling triggered by host perception in a plant pathogen

“…Previous studies in several fungal species have revealed roles for NO in global control of transcriptional and metabolic reprogramming and in modulating fungal morphogenesis and secondary metabolism 45–48 . To test if NO is involved in transcriptional regulation in Fg during the pre-contact stage, the NO inducibility of NR as well as several other pre-contact DEGs was analyzed in Fg by RT-qPCR after the application of the NO chemical donor S-Nitroso-N-acetyl-DL-penicillamine (SNAP).…”

“…NO can also serve as a key messenger and a signaling molecule favoring fitness of both fungal partner and plant hosts during pathogenic as well as mutualistic interactions 40,52–57 . Consequently, NO would deliver key messages from environmental signals and mediate the pathogen cellular responses through transcriptional reprogramming to facilitate lifestyle transition and niche adaptation 45–48 .…”

“…These observations suggest that FgANK1 is required for NO production as well as fungal development and virulence. It is possible that virulence and developmental alterations observed in the FgANK1 mutant could be due to defects in NO biosynthesis as NO has been implicated in these fungal processes in other fungi 38,41,42,48,55 . It is well documented that NO is an important signaling molecule that contributes to pathogen survival within the host 58 , and thus the loss-of-virulence phenotype of ΔFgANK1 could be due to the extreme sensitivity of this mutant to plant-defenses or the requirement of fungal-produced NO to interfere with plant defenses.…”

Horizontal gene transfer in the human and skin commensalMalassezia: a bacterially-derived flavohemoglobin is required for NO resistance and host interaction

“…Intracellular levels of NO was measured by flow cytometry adapted from previous method 62 . In brief, M. sympodialis WT and yhb1 Δ mutant were grown ON in mDixon media, washed once with PBS, and then incubated in PBS with agitation overnight.…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…In fact, mutant strains or chemical interventions in glycolysis (Rodaki et al, 2006;Laurian et al, 2019) or fatty acid biosynthesis (Xu et al, 2009) showed defective growth, suggesting that these metabolic pathways can be important targets. Other therapeutic options that target C. albicans metabolism is to trigger endogenous nitric oxide (NO) production using compounds such as mdivi-1, which represses hyphal growth and the yeast-to-hypha transition and promotes metabolic reprogramming in the fungus (Koch et al, 2018). During growth and morphogenesis, C. albicans relies on OxPhos to produce ATP and therefore, mitochondria can be targeted for new antifungal drugs (Duvenage et al, 2019a).…”