Candida albicans Pma1p Contributes to Growth, pH Homeostasis, and Hyphal Formation

Abstract

Candida albicans occupies diverse ecological niches within the host and must tolerate a wide range of environmental pH. The plasma membrane H + -ATPase Pma1p is the major regulator of cytosolic pH in fungi. Pma1p extrudes protons from the cytosol to maintain neutral-to-alkaline pH and is a potential drug target due to its essentiality and fungal specificity. We characterized mutants in which one allele of PMA1 has been deleted and the other truncated by 18–38 amino acids. Increasing C-terminal truncation caused corresponding decreases in plasma membrane ATPase-specific activity and cytosolic pH. Pma1p is regulated by glucose: glucose rapidly activates the ATPase, causing a sharp increase in cytosolic pH. Increasing Pma1p truncation severely impaired this glucose response. Pma1p truncation also altered cation responses, disrupted vacuolar morphology and pH, and reduced filamentation competence. Early studies of cytosolic pH and filamentation have described a rapid, transient alkalinization of the cytosol preceding germ tube formation; Pma1p has been proposed as a regulator of this process. We find Pma1p plays a role in the establishment of cell polarity, and distribution of Pma1p is non-homogenous in emerging hyphae. These findings suggest a role of PMA1 in cytosolic alkalinization and in the specialized form of polarized growth that is filamentation.

Candida albicans as an Essential “Keystone” Component within Polymicrobial Oral Biofilm Models?

“…As discussed above, C. albicans inclusion seemed to offer a buffering effect, as shown in the pH increase with the value closer to neutral in the supernatants collected ( Figure 4 ). Such a buffering effect is not unheard of with C. albicans , an organism which prefers to maintain a cytosolic pH range of between 5.8 and 9 [ 81 ]. Lactate and lactic acid are common metabolites of oral bacteria, and often a dysbiosis in the utilization and production of these compounds can lead to disease [ 82 ].…”

The Role of Fatty Acid Metabolites in Vaginal Health and Disease: Application to Candidiasis

“…This adaptability can potentially be explained by their broader cytosolic pH range. The cytosolic pH range of S. cerevisiae is between 6.0 and 7.0 while in C. albicans the intracellular pH range in vivo is wider, ranging between 5.8 and 9 (Cassone et al, 1983;Kaur et al, 1988;Stewart et al, 1988Stewart et al, , 1989Rabaste et al, 1995;Liu and Kohler, 2016;Tournu et al, 2017;Rane et al, 2019). Their growth is also less affected by an acidic cytosol compared to S. cerevisiae.…”

“…Their growth is also less affected by an acidic cytosol compared to S. cerevisiae. Rane et al (2019) it was shown that C. albicans cells with very acidic cytosols (pH ≤ 5.5) only show minimal growth defects. So SCFA probably exert their inhibitory effect on Candida species not by intracellular acidification alone.…”

The Role of Secretory Pathways in Candida albicans Pathogenesis

“…Removal of Pma1p from the plasma membrane prevents the spike in pH that signals filamentation. Recent work by Ranes et al [214] demonstrated that truncations of C. albicans Pma1p at the C-terminus leads to defects in proper localization and proton pumping activity of Pma1p. Loss of Pma1p function results in an acidification of the cytosol, and reduced filamentation.…”

“…Loss of Pma1p function results in an acidification of the cytosol, and reduced filamentation. Interestingly, the loss of Pma1p function results in hyper-acidification of the vacuole without altering the secretion of Saps and lipases [214].…”