Phosphoinositide signaling and regulation in Trypanosoma brucei: Specialized functions in a protozoan pathogen
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".