bims-toxgon 2026-04-26 papers

Issue of 2026–04–26
five papers selected by
Lakesh Kumar, BITS Pilani

Cell Rep. 2026 Apr 21. pii: S2211-1247(26)00377-3. [Epub ahead of print]45(5): 117299

TgSEC14-LTP1 is a vacuole-secreted SEC14/CRAL-TRIO-like protein required for host DAG flux and PC homeostasis in T. gondii.

Rosalba Cruz-Miron, Christopher Swale, Qinli Liang, Yoshiki Yamaryo-Botté, Christophe-Sébastien Arnold, Mohamed-Ali Hakimi, Cyrille Y Botté, Alexandre Bougdour, Jeroen P J Saeij.

Intracellular apicomplexan parasites depend on host-derived lipids to expand the parasitophorous vacuole (PV) and replicate. Toxoplasma gondii secretes numerous dense granule proteins (GRAs) for PV remodeling, but PV lumen factors that selectively bind host lipids and shape host-to-parasite lipid flux remain poorly defined. Here, we identify TgSEC14-LTP1, a previously uncharacterized GRA with a divergent SEC14/CRAL-TRIO domain. Structural and genetic analyses show that TgSEC14-LTP1 is secreted into the PV lumen and is essential for parasite replication. Lipidomic profiling, protein-lipid pulldown assays, 13C-labeling-based lipid flux analysis, and fluorescent lipid uptake assays show that TgSEC14-LTP1 binds phosphatidylcholine (PC) and diacylglycerol (DAG) and is required for efficient host-to-parasite PC and DAG flux and parasite lipid homeostasis. TgSEC14-LTP1 depletion reduces parasite PC and DAG pools, disrupts bulk PC synthesis and parasite biogenesis, delays egress, and ultimately impairs growth. These findings identify TgSEC14-LTP1 as a key Sec14-like PV lumen factor that links lipid binding to host lipid acquisition and PC homeostasis, underscoring the importance of host lipid scavenging for parasite survival.

Keywords: CP: Microbiology; DAG flux; PV-lumen; TgSEC14-LTP1; host-to-parasite PC; non-vesicular traffic; toxoplasma gondii

DOI: https://doi.org/10.1016/j.celrep.2026.117299

mBio. 2026 Apr 22. e0047526

Pyrophosphate homeostasis in multiple subcellular compartments is essential in Plasmodium falciparum.

Ikechukwu Nwankwo, Hangjun Ke.

Pyrophosphate is a byproduct of numerous cellular reactions that use ATP or other nucleoside triphosphates to synthesize DNA, RNA, protein, and various molecules. Its degradation into monophosphate is thus crucial for the survival and proliferation of all life forms. The human malaria parasite Plasmodium falciparum encodes two classes of pyrophosphatases to hydrolyze pyrophosphate. The first consists of P. falciparum proton pumping vacuolar pyrophosphatases (e.g., PfVP1), which localize to the parasite plasma membrane and work as proton pumps. The second includes P. falciparum soluble pyrophosphatases (PfsPPases), which have not been well characterized. Interestingly, the gene locus of PfsPPases encodes two isoforms, PfsPPase1 (PF3D7_0316300.1) and PfsPPase2 (PF3D7_0316300.2). PfsPPase2 contains a 51-amino acid organellar localization peptide that is absent in PfsPPase1. Here, we combine reverse genetics and biochemical approaches to identify the localization of PfsPPase1 and PfsPPase2 and elucidate their individual functions. We show that PfsPPases are essential for the asexual blood stages. While PfsPPase1 solely localizes to the cytoplasm, PfsPPase2 exhibits multiple localizations, including the mitochondrion, the apicoplast, and, to a lesser extent, the cytoplasm. Our data suggest that P. falciparum has taken a unique evolutionary trajectory in pyrophosphate metabolism by utilizing a leader sequence to direct sPPases to multiple organelles. This differs from model eukaryotes as they generally encode multiple sPPases at distinct genetic loci to facilitate pyrophosphate degradation in cytosolic and organellar compartments. The essentiality and divergence of PfsPPases also highlight them as promising targets for the development of novel antimalarial drugs.
IMPORTANCE: Malaria kills over 600,000 people annually. Understanding parasite biology is critical for identifying prospective drug targets. Malaria parasites maintain pyrophosphate (PPi) homeostasis in at least three subcellular compartments-the cytoplasm, mitochondrion, and apicoplast, where PPi is generated through various reactions. While cytoplasmic PPi is known to be degraded by soluble pyrophosphatase, it remains unclear how PPi is metabolized in the organelles of malaria parasites. Here, we discovered that Plasmodium falciparum encodes two soluble pyrophosphatase isoforms from a single genetic locus. The longer isoform contains an N-terminal leader sequence that targets the enzymes into the mitochondrion and the apicoplast. This dual targeting mechanism of soluble pyrophosphatases has not been previously reported in any organisms. We show that both isoforms are essential for parasite growth and development. These findings highlight the critical role of organellar PPi degradation and identify soluble pyrophosphatases as promising antimalarial drug targets.

Keywords: Plasmodium falciparum; apicoplast; cytoplasm; malaria; mitochondrion; pyrophosphate; soluble pyrophosphatase

DOI: https://doi.org/10.1128/mbio.00475-26

Immunohorizons. 2026 Apr 11. pii: vlag015. [Epub ahead of print]10(4):

ZBP1 mediated restriction of Toxoplasma gondii in both the early acute and chronic brain stages of infection.

Lydia Anne Sibley, Isaac William Babcock, Naa Dedee Amadi, Anne Elise Marchildon, Abigail Grace Kelly, Sydney Ann Labuzan, John Robert Lukens, Tajie Heartsong Harris.

ZBP1 is an innate sensor of nucleic acids in the Z-conformation and regulates immune responses via cell death pathways and nuclear factor κB signaling. Previous work has demonstrated an essential role for ZBP1 in viral restriction; however, the role ZBP1 plays in protection against other pathogens is in early stages of exploration. Toxoplasma gondii is an obligate intracellular parasite that can infect all nucleated cells and establishes a chronic infection of the brain requiring a robust innate and adaptive immune response and multiple cell death pathways for host survival. Importantly, innate sensors of T. gondii infection of the central nervous system are still being defined. Prior work has implicated caspase-1 and caspase-8 in the control of T. gondii in the brain. Because ZBP1 can activate both caspase-1 and caspase-8, we sought to explore the role of ZBP1 during T. gondii infection. During early infection, we found an increase in parasite burden; a decrease in NK1.1+ cell, neutrophil, and monocyte recruitment; and impaired NK1.1+ cell cytokine production in the peritoneum of Zbp1-/- mice. Interestingly, during the early adaptive immune response, the immune cell recruitment defects and impaired parasite control were ameliorated. During the brain stage of infection, ZBP1 regulated parasite restriction and numerous inflammatory responses to infection. Our findings establish ZBP1 as a critical regulator of host defense to T. gondii and highlight the importance of ZBP1 in development of inflammation during both the acute and chronic infection.

Keywords: Toxoplasma gondii ; ZBP1; neuroinflammation

DOI: https://doi.org/10.1093/immhor/vlag015

Nat Microbiol. 2026 Apr 22.

A single-cell atlas of Toxoplasma sexual development in the feline intestinal tract.

Hisham S Alrubaye, Sarah M Reilly, Rafaela da Silva, NyJaee Washington, Jon P Boyle.

Toxoplasma gondii undergoes sexual development exclusively in the feline intestine, a process critical for genetic diversity and population expansion. Recent studies have identified genes critical in suppressing presexual development and metabolic differences in felines that may promote sexual development, but to date, the gene regulatory networks driving development in the cat are unknown. To investigate this, we performed single-cell transcriptomics on parasites isolated from cat intestines, using fluorescent reporter strains and flow cytometry. From 15,068 cells across 2 experiments, we identified rare populations, including cells that bear all of the hallmarks of gametes. Candidate genes emerging from this study were tested via CRISPR-Cas9 perturb-seq, identifying AP2X6 as a regulator of macrogametocyte development. Our single-cell data extend what is known about gene expression changes throughout sexual development and should be useful to those in the field working towards inducing gametogenesis, mating and oocyst production in vitro.

DOI: https://doi.org/10.1038/s41564-026-02294-7

Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00367-0. [Epub ahead of print]45(5): 117289

Comprehensive mass spectrometry screening-derived atlas of HDAC inhibitors reveals histone-specific acetylation changes.

Rashmi Karki, Francisca N De Luna Vitorino, Richard M Searfoss, Joanna K Lempiäinen, Cheryl H Arrowsmith, Benjamin A Garcia.

Histone deacetylase inhibitors (HDACis) have emerged as valuable therapeutics for cancer and other diseases; however, their effects on histone post-translational modification remain poorly characterized. Here, we applied quantitative mass spectrometry and high-throughput sequencing to systematically profile site-specific changes in histone modifications in response to a panel of HDACis. This platform enabled mapping of histone modification changes across hundreds of sites, including low-abundance histone marks. Furthermore, an integrative analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) data identified genome-wide binding sites for the low-abundance histone modification of H2A.Z acetylation in HeLa and MDA-MB-231 breast cancer cells, highlighting the role of H2A.Z acetylation in regulating gene expression across diverse biological pathways, including specific genes involved in tumor suppressor pathways. Our findings provide a functional resource for identifying and quantifying histone modification changes and transcriptional regulation of histone H2A.Z acetylation following pharmacological perturbation.

Keywords: CP: genomics; ChIP-seq; Entinostat; RNA-seq; breast cancer; histone H2A.Z acetylation; histone deacetylase inhibitors; mass spectrometry; post-translational modification

DOI: https://doi.org/10.1016/j.celrep.2026.117289