Dataset Information

Quantitative TMT proteomics of myristoylated proteins in Trypanosoma cruzi and human cardiomyocytes during N-myristoyltransferase inhibition

ABSTRACT: This project investigates the impact of N-myristoyltransferase (NMT) inhibition on the myristoylated proteome of Trypanosoma cruzi and human cardiomyocytes in the context of Chagas disease. Human AC16 cardiomyocytes were infected with T. cruzi (CL Brener strain) and treated with the reference NMT inhibitor DDD85646 or vehicle control. Myristoylated proteins from intracellular amastigotes, extracellular trypomastigotes, and host cells were metabolically labeled with an azide-functionalized myristic acid analogue, enriched by click-chemistry, digested, and labeled with TMTsixplex reagents for multiplexed quantification. Labeled peptide fractions were analyzed by nanoLC–MS/MS on a Vanquish Neo UHPLC coupled to an Orbitrap Exploris 240 operated in data-dependent acquisition mode. The resulting dataset was used to quantify stage-specific changes in parasite and host myristoylated proteins upon TcNMT inhibition and to identify pathways related to vesicular trafficking, lipid metabolism, and signal transduction that are selectively perturbed in the parasite.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Trypanosoma Cruzi

TISSUE(S): Heart, Cardiac Muscle Cell

DISEASE(S): Chagas Disease

SUBMITTER: Angel Torres

LAB HEAD: Dr. Rosa A. Maldonado

PROVIDER: PXD071927 | Pride | 2026-01-26

REPOSITORIES: Pride

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Advancing Trypanosoma cruzi N-myristoyltransferase as a drug target for Chagas disease through in silico discovery and biochemical evaluation.

González García Diana D Torres Angel A Talevi Alan A Alberca Lucas N LN Beltran Miguel A MA Lara Frida F Da Silva Ferreira Marina M Farani Priscila S G PSG Almeida Igor C IC Maldonado Rosa A RA

Frontiers in molecular biosciences 20260106

<h4>Introduction</h4>N-myristoylation is a crucial lipid modification that governs protein localization, intracellular trafficking, and function in eukaryotic cells. The enzyme N-myristoyltransferase (NMT), which catalyzes this modification, has emerged as an attractive drug target for parasitic diseases. In this study, we performed a comprehensive biochemical and antiparasitic evaluation of Trypanosoma cruzi NMT (TcNMT), utilizing novel "in silico-identified inhibito ...[more]

PMID: 41567861

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Project description:The molecular mechanisms of Trypanosoma cruzi induced cardiac fibrosis remains to be elucidated. Primary human cardiomyoctes (PHCM) exposed to invasive T. cruzi trypomastigotes were used for transcriptome profiling and downstream bioinformatic analysis to determine fibrotic-associated genes regulated early during infection process (0 to 120 minutes). The identification of early molecular host responses to T. cruzi infection can be exploited to delineate important molecular signatures that can be used for the classification of Chagasic patients at risk of developing heart disease. Our results show distinct gene network architecture with multiple gene networks modulated by the parasite with an incline towards progression to a fibrogenic phenotype. Early during infection, T. cruzi significantly upregulated transcription factors including activator protein 1 (AP1) transcription factor network components (including FOSB, FOS and JUNB), early growth response proteins 1 and 3 (EGR1, EGR3), and cytokines/chemokines (IL5, IL6, IL13, CCL11), which have all been implicated in the onset of fibrosis. The changes in our selected genes of interest did not all start at the same time point. The transcriptome microarray data, validated by quantitative Real-Time PCR, was also confirmed by immunoblotting and customized Enzyme Linked Immunosorbent Assays (ELISA) array showing significant increases in the protein expression levels of fibrogenic EGR1, SNAI1 and IL 6. Furthermore, phosphorylated SMAD2/3 which induces a fibrogenic phenotype is also upregulated accompanied by an increased nuclear translocation of JunB. Pathway analysis of the validated genes and phospho-proteins regulated by the parasite provides the very early fibrotic interactome operating when T. cruzi comes in contact with PHCM. The interactome architecture shows that the parasite induces both TGF-Î² dependent and independent fibrotic pathways, providing an early molecular foundation for Chagasic cardiomyopathy. Examining the very early molecular events of T. cruzi cellular infection may provide disease biomarkers which will aid clinicians in patient assessment and identification of patient subpopulation at risk of developing Chagasic cardiomyopathy. Primary Human Cardiomyoctes (low passage) were exposed to T. cruzi at different time points. The control was done in biological triplicates and the time points (60, 90 and 120 minutes) were done in biological duplicates.

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Dataset Information

Quantitative TMT proteomics of myristoylated proteins in Trypanosoma cruzi and human cardiomyocytes during N-myristoyltransferase inhibition

Dataset's files

Publications

Advancing <i>Trypanosoma cruzi</i> N-myristoyltransferase as a drug target for Chagas disease through <i>in silico</i> discovery and biochemical evaluation.

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Dataset Information

Quantitative TMT proteomics of myristoylated proteins in Trypanosoma cruzi and human cardiomyocytes during N-myristoyltransferase inhibition

Dataset's files

Publications

Advancing &lt;i&gt;Trypanosoma cruzi&lt;/i&gt; N-myristoyltransferase as a drug target for Chagas disease through &lt;i&gt;in silico&lt;/i&gt; discovery and biochemical evaluation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Advancing <i>Trypanosoma cruzi</i> N-myristoyltransferase as a drug target for Chagas disease through <i>in silico</i> discovery and biochemical evaluation.