Inositol polyphosphate–protein interactions: Implications for microbial pathogenicity

Abstract

Inositol polyphosphates (IPs) and inositol pyrophosphates (PP-IPs) regulate diverse cellular processes in eukaryotic cells. IPs and PP-IPs are highly negatively charged and exert their biological effects by interacting with specific protein targets. Studies performed predominantly in mammalian cells and model yeasts have shown that IPs and PP-IPs modulate target function through allosteric regulation, by promoting intra-and intermolecular stabilization and, in the case of PP-IPs, by donating a phosphate from their pyrophosphate (PP) group to the target protein. Technological advances in genetics have extended studies of IP function to microbial pathogens and demonstrated that disrupting PP-IP biosynthesis and PP-IP-protein interaction has a profound impact on pathogenicity. This review summarises the complexity of IP-mediated regulation in eukaryotes, including microbial pathogens. It also highlights examples of poor conservation of IP-protein interaction outcome despite the presence of conserved IP-binding domains in eukaryotic proteomes. K E Y W O R D S fungal pathogens, inositol polyphosphate kinases, inositol polyphosphates, inositol pyrophosphates, microbial pathogenesis, protein modification 1 | INTRODUCTION IPs and PP-IPs are produced by a series of sequentially acting IP kinases (IPKs). Using genetic and pharmacological approaches to modulate IP kinase (IPK) activity in conjunction with gel-, HPLC-and, more recently, mass spectrometry-based metabolic profiling strategies, the identification and role of IPs and PP-IPs were initially elucidated in mammalian cells and the model yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe. IPK enzymatic function has also been confirmed in vitro using chemically synthesized substrates. These studies revealed that IPs and PP-IPs function in a diverse range of cellular processes including glucose homeostasis, insulin sensitivity and secretion, fat metabolism and cellular energy dynamics, growth factor signalling, phosphate homeostasis, vesicular trafficking, DNA damage and repair, chromatin remodelling, spermatogenesis, neuronal migration, neutrophil activity, aging, apoptosis and platelet function (Lee, Kim, Ahn, & Kim, 2020). Hence, it is not surprising that dysregulated IP and PP-IP biosynthesis in human cells is associated with numerous diseases including Huntington's disease (Ahmed et al., 2015), diabetes and obesity (Chakraborty et al., 2010) and cancer (Rao et al., 2015). Advances in genome sequencing and genome manipulation technology have subsequently allowed investigation into the roles of IPs and PP-IPs in microbial pathogenicity. The most significant progress has been in: Cryptococcus neoformans, an AIDS-related fungal pathogen and the most common cause of fungal meningitis worldwide (Rajasingham et al., 2017); Candida albicans, the commensal and opportunistic nosocomial pathogen and most prevalent cause of fungal infections worldwide (Bongomin, Gago, Oladele, &

Polyphosphate mobilization influences the ability ofCryptococcus neoformansto cause disease in a murine model of cryptococcosis

“…With key structural and signalling roles, inositol is an important nutrient for fungal pathogens and C. neoformans can use inositol as a sole carbon source (48). Inositol polyphosphates (IPs) and inositol pyrophosphates (PP-IPs) are involved in regulation of diverse cellular processes such as chromatin remodeling, calcium and phosphate homeostasis, and cell cycle (37). In Schizosaccharomyces pombe , inositol pyrophosphate is involved in phosphate homeostasis (49).…”

“…In S. cerevisiae (and other fungi), synthesis and vacuolar translocation of polyP is mediated by a polyP synthetase known as vacuolar transporter chaperone 4 or Vtc4 (5,36). Cells deficient in polyP synthetase have no detectable polyP and, for C. neoformans, this results in altered proliferation in the host and an impaired ability to trigger blood coagulation (37). Additionally, the genes XPP1 and EPP1 in C. neoformans encode putative exo- and endopolyphosphatases that catalyze the hydrolysis or mobilization of inorganic polyP in response to phosphate-limiting conditions (5).…”

Plasma Membrane Phosphatidylinositol 4-Phosphate Is Necessary for Virulence of Candida albicans

“…Although not as famous as the sugars that are more commonly involved in energy metabolism, such as glucose and fructose, inositol plays critical regulatory roles in the cytoplasm and in membranes, where it is used to modify lipids. Cytoplasmic inositol can be phosphorylated on all six carbon positions; some of these sites can be dually phosphorylated (pyrophosphorylated), as part of signaling mechanisms that stimulate a wide range of cellular functions ( 1 ). Inositol also forms part of the structure of membrane lipids, such as glycophosphatidylinositol modification (GPI anchor) of the C-terminal tails of cell surface proteins to anchor them in the plasma membrane, and inositol modification of ceramides to create new sphingolipid varieties.…”

TNP Analogues Inhibit the Virulence Promoting IP3-4 Kinase Arg1 in the Fungal Pathogen Cryptococcus neoformans

“…Recent studies in C. neoformans and C. albicans have shown that the inositol polyphosphate (IP) kinase (IPK) pathway is a promising target for antifungal drug development due to its involvement in numerous critical cellular processes (reviewed in [ 9 , 10 , 11 , 12 ]). The fungal IPK pathway is comprised of a series of sequentially acting IPKs that convert IP 3 to IP 8 , with IP 3-4 K the most critical for virulence and cellular function in both C. neoformans [ 13 , 14 , 15 , 16 ] and C. albicans [ 17 , 18 , 19 ].…”

“…In contrast to fungi, the product of IP 3-4 K, IP 5 , can be generated by more than one route in human and involves 4 different enzymes: inositol polyphosphate multikinase ( Hs IPMK), IP3K, INPP5 and ITPK1 (reviewed in [ 10 , 11 ]). In addition to having IP 3-4 K activity, Hs IPMK functions as a phosphoinositide 3-kinase [ 20 , 21 , 22 ] and as a scaffold protein in the target of rapamycin (TOR) where its enzymatic activity is not required [ 23 ] (reviewed in [ 24 ]).…”