Abstract
Invasive fungal pathogens cause more than 300 million serious human infections and 1.6 million deaths per year. A clearer understanding of the mechanisms by which these fungi cause disease is needed to identify novel targets for urgently needed therapies. Kinases are key components of the signaling and metabolic circuitry of eukaryotic cells, which include fungi, and kinase inhibition is currently being exploited for the treatment of human diseases. Inhibiting evolutionarily divergent kinases in fungal pathogens is a promising avenue for antifungal drug development. One such group of kinases is the phospholipase C1-dependent inositol polyphosphate kinases (IPKs), which act sequentially to transfer a phosphoryl group to a pre-phosphorylated inositol sugar (IP). This review focuses on the roles of fungal IPKs and their IP products in fungal pathogenicity, as determined predominantly from studies performed in the model fungal pathogen Cryptococcus neoformans, and compares them to what is known in non-pathogenic model fungi and mammalian cells to highlight potential drug targeting opportunities.
Highlights
Specialty section: This article was submitted to Fungal Pathogenesis, a section of the journal Frontiers in Cellular and Infection
This review focuses on the roles of fungal inositol polyphosphate kinases (IPKs) and their inositol polyphosphates (IPs) products in fungal pathogenicity, as determined predominantly from studies performed in the model fungal pathogen Cryptococcus neoformans, and compares them to what is known in non-pathogenic model fungi and mammalian cells to highlight potential drug targeting opportunities
The inositol polyphosphate kinases (IPKs), which are often confused with the phosphoinositide kinases, are distinct in that they phosphorylate a variety of cytosolic, water-soluble inositol polyphosphates (IPs) originating from the phosphatidylinositol head group
Summary
The fungal PHO pathway is activated when phosphate becomes scarce in the environment or at alkaline pH. There is some controversy as to which IP7 isoform is involved in PHO pathway activation: Lee et al demonstrated that ScVip1-derived IP7 (the 1-PP-IP5 isoform) interacts non-covalently with ScPho in the context of the ScPho80-Pho85-Pho complex, preventing Pho from accessing the kinase active site (Lee et al, 2007, 2008) Their data showed a corresponding increase in IP7 following phosphate deprivation. Ser in the dynein intermediate chain is pyrophosphorylated by IP7, and this modification promotes the interaction of dynein with the p150Glued subunit of dynactin, which recruits the motor to vesicles This mechanism provides an explanation for how PP-IPs affect intracellular vesicular trafficking in mammalian cells (Chanduri et al, 2016; Saiardi, 2016). These studies have paved the way for investigating the consequences of such interactions in promoting fungal pathogenesis
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