cAMP‐independent signal pathways stimulate hyphal morphogenesis in Candida albicans

Abstract

Summary The fungal pathogen Candida albicans can transition from budding to hyphal growth, which promotes biofilm formation and invasive growth into tissues. Stimulation of adenylyl cyclase to form cAMP induces hyphal morphogenesis. The failure of cells lacking adenylyl cyclase (cyr1Δ) to form hyphae has suggested that cAMP signaling is essential for hyphal growth. However, cyr1Δ mutants also grow slowly and have defects in morphogenesis, making it unclear whether hyphal inducers must stimulate cAMP, or if normal basal levels of cAMP are required to maintain cellular health needed for hyphal growth. Interestingly, supplementation of cyr1Δ cells with low levels of cAMP enabled them to form hyphae in response to the inducer N-acetylglucosamine (GlcNAc), suggesting that a basal level of cAMP is sufficient for stimulation. Furthermore, we isolated faster-growing cyr1Δ pseudorevertant strains that can be induced to form hyphae even though they lack cAMP. The pseudorevertant strains were not induced by CO2, consistent with reports that CO2 directly stimulates adenylyl cyclase. Mutational analysis showed that induction of hyphae in a pseudorevertant strain was independent of RAS1, but was dependent on the EFG1 transcription factor that acts downstream of protein kinase A. Thus, cAMP-independent signals contribute to the induction of hyphal responses.

Hyphal induction under the condition without inoculation in Candida albicans is triggered by Brg1‐mediated removal of NRG1 inhibition

“…E). Therefore, disruption of cAMP‐PKA signaling did not affect NRG1 transcriptional down‐regulation and GlcNAc‐induced filamentation, a finding which is consistent with the result of cAMP‐independent signal pathways in stimulating hyphal morphogenesis upon GlcNAc induction (Parrino et al ., ).…”

“…In addition to routine lab condition for hyphal induction which includes the dilution procedure, the yeast-tohypha transition could be also induced in the absence of inoculation. It is found that external stimuli, such as Nacetylglucosamine (GlcNAc), serum or neutral pH, are able to induce hyphal formation efficiently in log phase cells at 378C (Naseem et al, 2011;Su et al, 2016;Parrino et al, 2017). However, it is unknown how hyphal emergence can occur in log phase cells without inoculation.…”

“…It is also a powerful inducer of hyphal development in fungi (Sullivan and Shepherd, 1982;Kumar et al, 2000;Gilmore et al, 2013;Kappel et al, 2016). The effect of GlcNAc in hyphal induction is through a mechanism sensitive to inhibitors of cAMP-dependent protein kinase in C. albicans (Castilla et al, 1998), whereas only a normal basal level of cAMP, but not a pulse of cAMP-PKA activation, is needed (Parrino et al, 2017). Recent study reported that the GlcNAc-sensor and transducer Ngs1 is important for GlcNAc-induced hyphal development, especially hyphal transcription in log phase cells (Su et al, 2016;Naseem et al, 2017).…”

Regulation of Hyphal Growth and N-Acetylglucosamine Catabolism by Two Transcription Factors in Candida albicans

“…Interestingly, the mci4D and nuo1D mitochondrial mutants grew well in the presence of galactose plus GlcNAc, and could be induced to form hyphae (Figure 3). Although mitochondrial function has been linked to the cAMP pathway and regulation of hyphal growth (Morales et al 2013), it may not be important for GlcNAc to induce hyphae since this amino sugar can activate cAMP-independent pathways (Parrino et al 2017).…”

“…Previous studies suggested that the cAMP pathway might be involved in GlcNAc signaling, since a cyr1D mutant that lacks adenylyl cyclase is not induced by GlcNAc to form hyphae. However, a faster-growing pseudorevertant version of the cyr1D strain can be induced to form hyphae, indicating that GlcNAc can induce hyphal morphogenesis by cAMP-independent pathways (Parrino et al 2017).…”