pH signaling in human fungal pathogens: a new target for antifungal strategies

Abstract

Fungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signaling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signaling in C. albicans, A. fumigatus, and C. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signaling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition, and (v) to slow the emergence of resistant mutants.

FIG 1

Pal/Rim signaling cascades in Aspergillus nidulans, Saccharomyces cerevisiae, and Candida albicans. External pH sensing involves the plasma membrane complex, comprising PalH/Rim21-Dfg16 and its assistant, PalI/Rim9, an arrestin-like protein PalF/Rim8, and PalC/Rim23. At alkaline-neutral pH, the plasma membrane complex is endocytosed through PalF/Rim8 ubiquitination, which triggers interactions with the ESCRT complexes involved in the multivesicular body endocytic pathway. Vps32, a key component of ESCRT-III, interacts with PalC/Rim23 and PalA/Rim20. PalA/Rim20 in conjunction with PalB/Rim13 (the signaling protease) are members of the endosomal signaling complex and recruit PacC/Rim101. PalB/Rim13 mediates the cytoplasmic proteolysis of the full-length PacC/Rim101. In A. nidulans, a second processing event occurs independently of PalB. In all species, whether PalI/Rim9 is endocytosed together with PalC/Rim23, PalH/Rim21, and PalF/Rim8 has not been demonstrated. In C. albicans, the role of Vps23 has not been described. Also in C. albicans, Rim8 is not ubiquitinated but hyperphosphorylated and it associates with Rim21 and Rim101, suggesting a role in bridging the cortical and the endosomal signaling complexes.