Methionine is required for cAMP‐PKA‐mediated morphogenesis and virulence of Candida albicans

Abstract

Candida albicans is a major human fungal pathogen, causing superficial, as well as life-threatening invasive infections. Therefore, it has to adequately sense and respond to the host defense by expressing appropriate virulence attributes. The most important virulence factor of C. albicans is the yeast-to-hyphae morphogenetic switch, which can be induced by numerous environmental cues, including the amino acid methionine. Here, we show an essential role for methionine permease Mup1 in methionine-induced morphogenesis, biofilm formation, survival inside macrophages and virulence. Furthermore, we demonstrate that this process requires conversion of methionine into S-adenosyl methionine (SAM) and its decarboxylation by Spe2. The resulting amino-propyl group is then used for biosynthesis of polyamines, which have been shown to activate adenylate cyclase. Inhibition of the SPE2 SAM decarboxylase gene strongly impairs methionine-induced morphogenesis on specific media and significantly delays virulence in the mouse systemic infection model system. Further proof of the connection between methionine uptake and initial metabolism and the cAMP-PKA pathway was obtained by showing that both Mup1 and Spe2 are required for cAMP production in response to methionine. Our results suggest that amino acid transport and further metabolism are interesting therapeutic targets as inhibitors of this may prevent the morphogenetic switch, thereby preventing virulence.

Sugar Sensing and Signaling in Candida albicans and Candida glabrata

“…This raises the question about which ligand is able to activate Ca Gpr1. The lab of Van Dijck showed that methionine might be the ligand of Ca Gpr1 as this receptor is required for the methionine-induced and PKA mediated morphogenesis (Maidan et al, 2005a; Schrevens et al, 2018). Furthermore, it was shown that Ca Gpr1 internalizes in the presence of methionine, indicating ligand-induced internalization (Maidan et al, 2005a).…”

Recent advances in understanding Candida albicans hyphal growth

“…In the past 2 to 3 years, a range of studies have investigated hyphal growth signaling in C. albicans 35 . These studies have made significant advances, in particular in the areas of amino acid inducers of the hyphal transition 36, 37 , gaseous sensing and signaling 38– 42 , and reactive oxygen and oxidative stress signaling 43– 45 . Extensive analyses of filamentation programs revealed media-independent genetic requirements for filamentation, in particular RIM101 (pH-dependent pathway) and GPA2 (Gα functioning in the cAMP/PKA pathway), in addition to a core transcriptional profile 46 .…”

Conserved and Divergent Functions of the cAMP/PKA Signaling Pathway in Candida albicans and Candida tropicalis

“…Inhibition of mitochondrial activity resulted in reduced Ras1 and Cyr1 activity and consequently attenuated filamentation [ 89 ]. In addition, other proteins, such as Hsp90 and its co-activator Sgt1, regulate morphogenesis and drug tolerance in C. albicans [ 30 , 90 ], and small chemical compounds have also been found to control its morphogenesis via the cAMP/PKA pathway [ 91 , 92 , 93 ]. Furthermore, as the cAMP/PKA pathway is conserved in eukaryotic cells and regulates virulence in C. albicans and C. tropicalis , this pathway might be a promising target for antifungal drug development.…”