Calcium-Calmodulin-Calcineurin Signaling: A Globally Conserved Virulence Cascade in Eukaryotic Microbial Pathogens

Abstract

Calcium is an abundant intracellular ion, and calcium homeostasis plays crucial roles in several cellular processes. The calcineurin signaling cascade is one of the major pathways governed by intracellular calcium. Calcineurin, a conserved protein from yeast to humans, is a calcium-calmodulin-dependent serine-threonine-specific phosphatase that orchestrates cellular stress responses. In eukaryotic microbial pathogens, calcineurin controls essential virulence pathways, such as the ability to grow at host temperature, morphogenesis to enable invasive hyphal growth, drug tolerance and resistance, cell wall integrity, and sexual development. Therefore, the calcineurin cascade is an attractive target in drug development against eukaryotic pathogens. In the present review, we summarize and discuss the current knowledge on the roles of calcineurin in eukaryotic microbial pathogens, focusing on fungi and parasitic protists.

Figure 1.. The calcineurin signaling pathway in mammals, fungi, and protists.

In response to external or internal signals, intracellular calcium concentrations increase via uptake from the extracellular milieu or by release from intracellular stores. Calcium ions bind to the calcium binding protein calmodulin, which in turn binds to and stimulates calcineurin protein phosphatase activity. Activated calcineurin dephosphorylates target proteins, including NFAT and Crz1, enabling appropriate cellular responses.

Figure 2.. Functions of the calcineurin signaling pathway in S. cerevisiae, C. neoformans, A. fumigatus, and C. albicans.

The phenotypes and functions attributed to calcineurin signaling in fungal species occur via Crz1-dependent and Crz1-independent pathways. In each species, some calcineurin functions are mediated via Crz1, while others are independent of Crz1 and mediated by other calcineurin targets.