Abstract
Trypanosoma brucei is a single-celled protozoan pathogen that causes human and animal trypanosomiasis and incurs devastating health and economic burdens in Africa. Together with the related parasites T. cruzi and Leishmania spp., which cause Chagas disease and leishmaniasis, respectively, over 8 million people are affected annually worldwide [1]. These parasites alternate between a mammalian host and the insect vector and undergo extensive developmental changes during their life cycle, including changes in surface coat, gene expression, metabolism, and organelle morphology and function. They also have elaborate mechanisms of gene regulation that control the expression of genes involved in host immune evasion during infection. The control of developmental changes and immune evasion mechanisms entails a complex network of signaling and regulatory processes that includes phosphatidylinositol (PI) phosphates (PIP, also called phosphoinositides) and inositol phosphates (IP) [2–8]. PIPs and IPs are ubiquitous in eukaryotes and consist of a subset of molecules containing mono or poly phosphorylated inositol (Fig 1A). Whilst PIPs are a class of phospholipids generally associated with cellular or organellar membranes and produced via phosphorylation of PI, IPs are soluble molecules produced as a result of PIP hydrolysis by phospholipase enzymes. PIPs and IPs interact with proteins or RNA and regulate numerous cellular functions in eukaryotes. As detailed below, these metabolites and related enzymes function as a regulatory system with essential roles in T. brucei metabolism and development [6], trafficking and organelle biogenesis [9–11], Ca2+ signaling [12], and immune evasion mechanisms [5, 7]. Open in a separate window Fig 1 PIP and IP synthesis and regulation in T. brucei. (A) Structure of PIP2 indicated by the inositol ring (black hexagon), phosphates (red circles), and DAG with fatty acid chain. PLC cleaves PIP2 and produces diacylglycerol and IP3. Black arrows indicate phosphate and inositol. The yellow arrow indicates the site of PLC cleavage, which occurs between DAG and phosphate sn1. The green arrow indicates the directionality of the PLC reaction. (B) The number of genes involved in PIP and IP synthesis, signaling (includes PLC and IP3 receptors), and PIP and IP kinases and phosphatases in eukaryotes and prokaryotes. The size of the black circles indicates the number of genes in each category. (C) Synthesis of PIPs and IPs based on T. brucei predicted and characterized enzymes. Enzymes, whose regulatory functions are discussed here, are indicated in blue. PIP-Pase indicates enzymes that dephosphorylate PIPs at positions 3, 4, or 5 of the inositol ring. It includes PIP5Pase, whose catalytic activity is detailed below in D. Metabolite short names are used for simplicity. (D) Regulation of VSG silencing by PIP5Pase. PIP5Pase dephosphorylates the 5-phosphate (green circle) of PIP3 and prevents this metabolite binding to RAP1, which preserves RAP1 function (and likely other proteins) in ES chromatin organization. Catalytic inactivation of PIP5Pase results in PIP3 binding to RAP1, which affects ES chromatin organization and results in transcription of VSG genes. 1, diacylglycerol kinase; 2, cytidine diphosphate-diacylglycerol synthase; 3, phosphatidylinositol synthase; 70 bp, 70 base pair repeats; Ath, Arabidopsis thaliana; DAG, diacylglycerol; ER, endoplasmic reticulum; ES, expression site; ESAG, expression site associated genes; Hsp, Homo sapiens; I, myo-inositol; IMPase, inositol monophosphatase; IP, inositol phosphate; IP1, D-myo-inositol 1-monophosphate; IP2, D-myo-inositol 1,4-diphosphate; IP3, D-myo-inositol 1,4,5-triphosphate; IP4, D-myo-inositol 1,3,4,5-tetrakisphosphate; IP5, D-myo-inositol 1,2,3,4,5-pentakisphosphate; IP5Pase, inositol polyphosphate 5-phosphatase; IP6, D-myo-inositol 1,2,3,4,5,6-hexakisphosphate; IP6K, inositol hexakisphosphate kinase; IP7, D-myo-inositol 5-diphospho 1,2,3,4,6-pentakisphosphate; IPMK, inositol polyphosphate multikinase; Mtb, Mycobacterium tuberculosis; PIP, phosphatidylinositol phosphate; PIP1, phosphatidylinositol 4-phosphate; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PIP5K, phosphatidylinositol phosphate 5-kinase; PIP5Pase, phosphatidylinositol phosphate 5-phosphatase; PIP-Pase, phosphatidylinositol phosphate phosphatases; PLC, Phospholipase C; PM, plasma membrane; Pol I, RNA polymerase I; PP-IP4, D-myo-inositol 5-diphospho 1,3,4,6-tetrakisphosphate; RAP1, repressor-activator protein 1; Sce, Saccharomyces cerevisiae; sn1, unimolecular nucleophilic substitution; Tbr, T. brucei; Ttm, Thermus thermophilus; VSG, variant surface glycoprotein.
Highlights
Trypanosoma brucei is a single-celled protozoan pathogen that causes human and animal trypanosomiasis and incurs devastating health and economic burdens in Africa
PIPs and inositol phosphates (IP) have diversified in function to control specialized processes such as antigenic variation in T. brucei [5, 7]
The finding that Phosphatidylinositol phosphate 5-kinase (PIP5K) and phospholipase C (PLC) control variant surface glycoproteins (VSGs) expression and switching raises the question of whether a signal transduction system is involved in the control of antigenic variation
Summary
Citation: Cestari I (2020) Phosphoinositide signaling and regulation in Trypanosoma brucei: Specialized functions in a protozoan pathogen. PLoS Pathog 16(1): e1008167. https://doi.org/ 10.1371/journal.ppat.1008167 Editor: Laurie Read, University at Buffalo School of Medicine and Biomedical Sciences, UNITED STATES Funding: This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2019-04658); NSERC Discovery Launch Supplement for Early Career Researchers (DGECR-2019-00081) and by McGill University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
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