bims-toxgon 2024-10-27 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2024–10–27
29 papers selected by
Lakesh Kumar, BITS Pilani

The emerging role of Toxoplasma gondii in periodontal diseases and underlying mechanisms.
Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy.
T lymphocyte-dependent IL-10 down-regulates a cytokine storm driven by Toxoplasma gondii GRA24.
BONCAT-iTRAQ Labelling Reveals Molecular Markers of Adaptive Responses in Toxoplasma gondii to Pyrimethamine Treatment.
[Formula: see text]Mouse innate resistance to Neospora caninum infection is driven by early production of IFNγ by NK cells in response to parasite ligands.
Insights Into the Molecular Interactions of MIC2 and M2AP: Role of TSR6 and Conservation Across Species.
Toxoplasma gondii infection induces the expression of the chemokine CXCL16 in macrophages to promote chemoattraction of CXCR6+ cells.
Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection.
Levonorgestrel enhanced Toxoplasma gondii infection risk via progesterone receptor upregulation.
Plant-derived compounds that target histone acetyltransferases inhibit Trypanosoma cruzi proliferation and viability and affect parasite ultrastructure.
Toxoplasma WH3 Δrop18 acts as a live attenuated vaccine against acute and chronic toxoplasmosis.
Toxoplasma gondii macrophage migration inhibitory factor shows anti-Mycobacterium tuberculosis potential via AZIN1/STAT1 interaction.
Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer activities.
The Plasmodium falciparum histone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood-stage parasites.
HDAC8 as a target in drug discovery: Function, structure and design.
Histone deacetylases: potential therapeutic targets in cisplatin-induced acute kidney injury.
Dissecting the role of transcription factor AP2-M in Babesia asexual replication.
Advancing Native Mass Spectrometry Toward Cellular Biology.
HDAC7 promotes ovarian cancer malignancy via AKT/mTOR signalling pathway.
From Trypomastigotes to Trypomastigotes: Analyzing the One-Way Intracellular Journey of Trypanosoma cruzi by Ultrastructure Expansion Microscopy.
Gene Expression Tradeoffs Determine Bacterial Survival and Adaptation to Antibiotic Stress.
Characterization of two Plasmodium falciparum lipid transfer proteins of the Sec14/CRAL-TRIO family.
Molecular mechanisms of polarized transport to the apical plasma membrane.
Exploring the role of N-acetyltransferases in diseases: a focus on N-acetyltransferase 9 in neurodegeneration.
dCas9-HDAC8-EGFP fusion enables epigenetic editing of breast cancer cells by H3K9 deacetylation.
The Plasmodium falciparum histone methyltransferase SET10 participates in a chromatin modulation network crucial for intraerythrocytic development.
Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.
Acetylation of DnaJ facilitates the proliferation of BmNPV by affecting the transport of nucleocapsids.
Effects of phospholipase D1 inhibitory peptide on the growth and metastasis of gastric cancer cells.

Front Immunol. 2024 ;15 1464108

The emerging role of Toxoplasma gondii in periodontal diseases and underlying mechanisms.

Henglong Cao, Jianfeng Lin, Hao Yuan, Zipeng Yang, Min Nie, Janak L Pathak, Zi-Guo Yuan, Miao Yu.

  Toxoplasma gondii (T. gondii), an obligate intracellular protozoan parasite, is increasingly recognized for its role in various human diseases, including periodontal diseases. Periodontal diseases comprise a wide range of inflammatory conditions that not only affect the supporting structures of the teeth and oral health but also contribute to systemic diseases. The parasite's ability to modulate the host's immune response and induce chronic inflammation within the periodontium is a key factor in periodontal tissue damage. Through its virulence factors, T. gondii disrupts the balance of inflammatory cytokines, leading to dysregulated immune responses, and exacerbates oxidative stress in periodontal tissues. And T. gondii invasion could affect specific proteins in host cells including HSP70, BAGs, MICs, ROPs, SAGs, and GRAs leading to periodontal tissue damage. The indirect role of the host immune response to T. gondii via natural killer cells, monocytes, macrophages, neutrophils, dendritic cells, T cells, and B cells also contributes to periodontal diseases. Understanding these complex interactions of T. gondii with host cells could unravel disease mechanisms and therapeutic targets for periodontal diseases. This review delves into the pathogenic mechanisms of T. gondii in periodontal diseases, offering a detailed exploration of both direct and indirect pathways of its impact on periodontal health.

Keywords:  T. gondii; cytokines; immune response; inflammation; pathogenic mechanisms; periodontitis

DOI:  https://doi.org/10.3389/fimmu.2024.1464108
Pathogens. 2024 Oct 14. pii: 898. [Epub ahead of print]13(10):

Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy.

Miki Miyagaki, Yuan Zong, Mingming Yang, Jing Zhang, Yaru Zou, Kyoko Ohno-Matsui, Koju Kamoi.

  Toxoplasma gondii, an obligate intracellular parasite, is a globally prevalent pathogen capable of infecting a wide range of warm-blooded animals, including humans. Ocular toxoplasmosis (OT), a severe manifestation of T. gondii infection, can lead to potentially blinding complications. This comprehensive review delves into the current understanding of T. gondii biology, exploring its complex life cycle, diverse transmission routes, and strain diversity. This article provides an in-depth analysis of the clinical manifestations of OT, which can result from both congenital and acquired infections, presenting a spectrum of signs and symptoms. The review examines various diagnostic strategies employed for OT, including clinical examination, multimodal imaging techniques such as fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA), as well as laboratory tests including serology and molecular methods. Despite extensive research, the specific mechanisms underlying ocular involvement in T. gondii infection remain elusive, and current diagnostic options have limitations. Moreover, the treatment of active and recurrent OT remains a challenge. While existing therapies, such as antimicrobial agents and immunosuppressants, can control active infections, they do not offer a definitive cure or completely prevent recurrence. The clinical endpoints for the management of active and recurrent OT are also not yet well-established, and the available treatment methods carry the potential for adverse effects. This article highlights the need for future research to elucidate the pathogenesis of OT, investigate genetic factors influencing susceptibility to infection, and develop more sensitive and specific diagnostic tools. Enhancing global surveillance, implementing robust prevention strategies, and fostering multidisciplinary collaborations will be crucial in reducing the burden of OT and improving patient outcomes. This comprehensive review aims to provide a valuable resource for clinicians, researchers, and policymakers, contributing to a better understanding of T. gondii infection and its impact on ocular health.

Keywords:  Diagnostic techniques; Ocular toxoplasmosis; Pathogenesis research; Toxoplasma gondii

DOI:  https://doi.org/10.3390/pathogens13100898
mBio. 2024 Oct 23. e0145524

T lymphocyte-dependent IL-10 down-regulates a cytokine storm driven by Toxoplasma gondii GRA24.

Claire M Doherty, Paige R Patterson, Julie A Emeanuwa, Jessica Belmares Ortega, Barbara A Fox, David J Bzik, Eric Y Denkers.

  As a model organism in the study of immunity to infection, Toxoplasma gondii has been instrumental in establishing key principles of host anti-microbial defense and its regulation. Here, we employed an attenuated uracil auxotroph strain of Type I Toxoplasma designated OMP to further untangle the early immune response to this parasitic pathogen. Experiments using αβ T cell-deficient Tcrb-/- mice unexpectedly revealed that an intact αβ T lymphocyte compartment was essential to survive infection with OMP. Subsequent antibody depletion and knockout mouse experiments demonstrated contributions from CD4+ T cells and most predominantly CD8+ T cells in resistance. Using transgenic knockout mice, we found only a partial requirement for IFN-γ and a lack of requirement for Toll-like receptor (TLR) adaptor MyD88 in resistance. In contrast to other studies on Toxoplasma, the ability to survive OMP infection did not require IL-12p40. Surprisingly, T cell-dependent IL-10 was found to be critical for survival, and deficiency of this cytokine triggered an abnormally high systemic inflammatory response. We also found that parasite molecule GRA24, a dense granule protein that triggers TLR-independent IL-12 production, acts as a virulence factor contributing to death of OMP-infected Tcrb-/- and IL-10-/- mice. Furthermore, resistance against OMP was restored in Tcrb-/- mice via monoclonal depletion of IL-12p40, suggesting that GRA24-induced IL-12 underlies the fatal immunopathology observed. Collectively, our studies provide insight into a novel and rapidly arising T lymphocyte-dependent anti-inflammatory response to T. gondii which operates independently of MyD88 and IL-12 and that depends on the function of parasite-dense granule protein GRA24.IMPORTANCEAs a model infectious microbe and an important human pathogen, the apicomplexan Toxoplasma gondii has provided many important insights into innate and adaptive immunity to infection. We show here that a low virulence uracil auxotrophic Toxoplasma strain emerges as a virulent parasite in the absence of an intact T cell compartment. Both CD4+ and CD8+ T lymphocytes are required for optimal protection, in line with previous findings in other models of Toxoplasma infection. Nevertheless, several novel aspects of the response were identified in our study. Protection occurs independently of IL-12 and MyD88 and only partially requires IFN-γ. This is noteworthy particularly because the cytokines IL-12 and IFN-γ have previously been regarded as essential for protective immunity to T. gondii. Instead, we identified the anti-inflammatory effects of T cell-dependent IL-10 as the critical factor enabling host survival. The parasite dense granule protein GRA24, a host-directed mitogen-activated protein kinase activator, was identified as a major virulence factor in T cell-deficient hosts. Collectively, our results provide new and unexpected insights into host resistance to Toxoplasma.

Keywords:  T-cell immunity; Toxoplasma gondii; cytokines

DOI:  https://doi.org/10.1128/mbio.01455-24
Pathogens. 2024 Oct 08. pii: 879. [Epub ahead of print]13(10):

BONCAT-iTRAQ Labelling Reveals Molecular Markers of Adaptive Responses in Toxoplasma gondii to Pyrimethamine Treatment.

John G Mina, Anutthaman Parthasarathy, Exequiel O Porta, Paul W Denny, Karunakaran Kalesh.

  We employed a BONCAT-iTRAQ labelling approach to investigate newly synthesised proteins (NSPs) in Toxoplasma gondii subjected to varying concentrations of the antifolate drug pyrimethamine. Our results reveal that numerous NSPs exhibited altered expression levels in response to the drug, with significant upregulation observed at higher concentrations. Key proteins involved in protein synthesis, stress responses, energy metabolism, and cytoskeletal dynamics were identified, indicating that T. gondii undergoes complex adaptive responses to pyrimethamine treatment. While some of the identified pathways reflect a generic stress response, this study provides important molecular markers and mechanistic insights specific to the parasite's adaptation strategies. These findings contribute to understanding how T. gondii modulates its proteome in response to drug-induced stress and lay the groundwork for further investigations into potential therapeutic targets.

Keywords:  BONCAT; Toxoplasma gondii; iTRAQ; pyrimethamine; quantitative proteomics

DOI:  https://doi.org/10.3390/pathogens13100879
mSphere. 2024 Oct 24. e0025524

[Formula: see text]Mouse innate resistance to Neospora caninum infection is driven by early production of IFNγ by NK cells in response to parasite ligands.

R S Coombs, A E Overacre-Delgoffe, A Bhattacharjee, T W Hand, J P Boyle.

  Toxoplasma gondii is capable of being transmitted by nearly all warm-blooded animals, and rodents are a major source of parasite dissemination, yet mechanisms driving its broad host range are poorly understood. Although a phylogenetically close relative of T. gondii, Neospora caninum differs from T. gondii in that it does not infect mice and only infects a small number of ruminant and canine species. We recently showed that T. gondii and N. caninum grow similarly in mice during the first 24 h post-infection, but only N. caninum induces an IFNγ-driven response within hours that controls the infection. The goal of the present study was to understand the cellular basis of this rapid response to N. caninum. To do this, we compared immune cell populations at the site of infection 4 h after T. gondii or N. caninum infection in mice. We found that both parasites induced similar frequencies of peritoneal monocytes, while macrophages and dendritic cell populations were not increased compared to uninfected mice. Through a series of knockout mouse experiments, we show that B, T, and NKT cells are not required for immediate IFNγ production and ultimate control of N. caninum infection, suggesting that natural killer (NK) cells are the primary inducers of immediate IFNγ in response to N. caninum. N. caninum infections exhibited significantly more IFNγ+ NK cells in the peritoneum compared with T. gondii-infected and uninfected mice. Finally, we demonstrate that differences in early IFNγ production during N. caninum and T. gondii infections in mice are at least partly due to differences in soluble antigen(s) produced by tachyzoites.
IMPORTANCE: Pathogen differences in host range are poorly understood at the molecular level even though even closely related pathogen species can have dramatically distinct host ranges. Here, we study two related parasite species that have a dramatic difference in their ability to infect mice. Here, we show that soluble proteins from these species determine one driver of this difference: induction of interferon gamma by cells of the innate immune system.

Keywords:  Neospora caninum; Toxoplasma gondii; innate immune response; interferon γ; natural killer cells

DOI:  https://doi.org/10.1128/msphere.00255-24
Proteins. 2024 Oct 22.

Insights Into the Molecular Interactions of MIC2 and M2AP: Role of TSR6 and Conservation Across Species.

Xu Xia, Chenqiang Du, Yang Wang, Gaojie Song.

  Microneme protein 2 (MIC2) and its associated protein M2AP are pivotal for the gliding motility and host cell invasion by Toxoplasma gondii. In our prior work, we showed that M2AP binds specifically to the sixth TSR domain of MIC2, with this interaction mediated dominantly by the hotspot residue H620 situated at the center of TSR6. To delve deeper into the functional significance of H620 and explore the dynamic behavior of Y602, we conducted molecular dynamic (MD) simulations of the Toxoplasma TSR6-M2AP complex, encompassing both wild-type and mutant forms. Our findings underscore the critical role of H620 within TSR6, particularly its hydrogen bond interaction with K72 of M2AP. The H620A mutation disrupts the nearby hydrophobic network while minimally affecting other hydrophilic interactions. Furthermore, our data reveal a highly conserved binding pose between M2AP and TSR6 across different species, consistent with previous trans-genera studies, thereby offering insights for future strategies in infection control development.

Keywords:   Toxoplasma gondii ; ITC; M2AP; MD simulations; MIC2

DOI:  https://doi.org/10.1002/prot.26758
Infect Immun. 2024 Oct 22. e0030924

Toxoplasma gondii infection induces the expression of the chemokine CXCL16 in macrophages to promote chemoattraction of CXCR6+ cells.

Louis-Philippe Leroux, Visnu Chaparro, Alexandra Plouffe, Brent Johnston, Maritza Jaramillo.

  CXCL16 is a multifaceted chemokine expressed by macrophages and other immune cells in response to viral and bacterial pathogens. However, few studies have investigated its role in parasitic infections. The obligate intracellular parasite Toxoplasma gondii (T. gondii) is the causative agent of toxoplasmosis, an infection with potentially deleterious consequences in immunocompromised individuals and the developing fetus of acutely infected pregnant women. Chemokines are critical mediators of host defense and, as such, dysregulation of their expression is a subversion strategy often employed by the parasite to ensure its survival. Herein, we report that types I and II T. gondii strains upregulated the expression of both transmembrane and soluble forms of CXCL16 in infected bone marrow-derived macrophages (BMDM). Exposure to soluble T. gondii antigens (STAg) and to excreted-secreted proteins (TgESP) led to the induction of CXCL16. Cxcl16 mRNA abundance and CXCL16 protein levels increased in a time-dependent manner upon T. gondii infection. Importantly, conditioned medium (CM) collected from T. gondii-infected wild-type (WT) macrophage cultures promoted the migration of RAW264.7 cells expressing CXCR6, the cognate receptor of CXCL16, an effect that was significantly reduced by a neutralizing anti-CXCL16 antibody or use of CM from CXCL16 knockout (KO) macrophages. Lastly, T. gondii-driven CXCL16 expression appeared to modulate cytokine-induced (IL-4 + IL-13) alternative macrophage activation and M2 phenotypic marker expression. Further investigation is required to determine whether this chemokine contributes to the pathogenesis of toxoplasmosis and to elucidate the underlying molecular mechanisms.

Keywords:  CXCL16; CXCR6; Toxoplasma gondii; chemokine; inflammation; macrophage

DOI:  https://doi.org/10.1128/iai.00309-24
PLoS Pathog. 2024 Oct 24. 20(10): e1012006

Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection.

Isaac W Babcock, Lydia A Sibley, Sydney A Labuzan, Maureen N Cowan, Ish Sethi, Seblework Alemu, Abigail G Kelly, Michael A Kovacs, John R Lukens, Tajie H Harris.

Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release. Toxoplasma gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-γ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1-positive cells drives IL-18 release, which potentiates CD4+ T cell IFN-γ production and parasite control. Notably, our Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored CD4+ T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii.

DOI: https://doi.org/10.1371/journal.ppat.1012006
Vet Parasitol. 2024 Oct 10. pii: S0304-4017(24)00219-X. [Epub ahead of print]332 110330

Levonorgestrel enhanced Toxoplasma gondii infection risk via progesterone receptor upregulation.

Shenghui Wang, Tiancong Sun, Yan Huang, Rongsheng Mi, Yan Zhang, Haiyan Gong, Zhaoguo Chen.

  The numerous stray cats and dogs worldwide pose a huge burden on local governments, keeping residents safe and healthy, and maintaining clean cities with good traffic situations. To effectively control the populations of these stray animals, while considering animal welfare, researchers have suggested the use of levonorgestrel (LNG) as a contraceptive method. However, the potential side effects of LNG on these animals need to be evaluated before widespread application. Since dogs and cats play important roles in the transmission of Toxoplasma gondii as intermediate and definitive hosts, respectively, it is critical to assess the safety of LNG from the perspective of its effect on Toxoplasma susceptibility. In this study, the susceptibility of mice to T. gondii infection was investigated in vivo and in vitro with the presence of LNG. As a result, LNG increased the risk of infection, which was probably associated with the downregulation of IFN-γ levels, but not with the alteration of host sex hormone levels. Concurrently, the presence of LNG enhanced the expression of its ligand, the progesterone receptor (PGR), on the host cells. The promotional effect of LNG on T. gondii infection was attenuated when the PGR gene was knocked down. This investigation represents the inaugural study of LNG's side effects on T. gondii infection in mice, underscoring the significance of choosing or developing suitable contraceptive drugs for stray animals.

Keywords:  Levonorgestrel; Progesterone receptor; Susceptibility; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.vetpar.2024.110330
Micron. 2024 Oct 17. pii: S0968-4328(24)00146-X. [Epub ahead of print]188 103729

Plant-derived compounds that target histone acetyltransferases inhibit Trypanosoma cruzi proliferation and viability and affect parasite ultrastructure.

Fernanda Pereira Bortolami, Aline Araujo Zuma, Wanderley de Souza, Maria Cristina Machado Motta.

  Trypanosoma cruzi, the causative agent of Chagas disease, exhibits a chromatin structure and organization similar to that of other eukaryotes, undergoing certain epigenetic modifications, such as histone acetylation and deacetylation. Histone acetyltransferase inhibitors have been frequently applied as therapy agents against tumor cells, but their effects on protozoa have not yet been adequately explored. In this study, the effects of three acetyltransferase inhibitors, curcumin, triptolide and anacardic acid, were investigated on T. cruzi. Curcumin was able to inhibit epimastigote and amastigote proliferation and was the most effective compound. Triptolide also impaired T. cruzi proliferation and, along with curcumin, promoted the unpacking of nuclear heterochromatin and nucleolus disorganization. Anacardic acid did not alter parasite growth or viability, but caused ultrastructural changes, such as mitochondrial swelling and cristae enlargement. None of these compounds affected the microtubule cytoskeleton. These findings indicate that histone acetyltransferase inhibitors, especially curcumin, display the potential to be applied in chemotherapeutic studies against T. cruzi. Our results reinforce the necessity of developing new compounds that can be used successfully in therapy against neglected diseases.

Keywords:  Acetyltransferase inhibitors; Chromatin condensation; Epigenetic modification; Histone; Trypanosoma cruzi; Ultrastructure

DOI:  https://doi.org/10.1016/j.micron.2024.103729
NPJ Vaccines. 2024 Oct 23. 9(1): 197

Toxoplasma WH3 Δrop18 acts as a live attenuated vaccine against acute and chronic toxoplasmosis.

Cong Wang, Shengnan Fu, Xin Yu, Hang Zhou, Famin Zhang, Lingling Song, Ji Zhao, Yun Yang, Jianbing Du, Qingli Luo, Jilong Shen, Li Yu.

Toxoplasma gondii is a significant zoonotic pathogen of toxoplasmosis in humans and animals. Here a live attenuated Toxoplasma vaccine of WH3 Δrop18 was developed. The results showed that all mice vaccinated with WH3 Δrop18 were able to survive when challenge with various strains of Toxoplasma, including RH (type I), ME49 (type II), WH3 or WH6 (type Chinese 1). No cysts, if few, in the brain of the vaccinated animals were seen after challenge with cyst forming strains of ME49 or WH6. Vaccination with the WH3 Δrop18 triggered a strong immune response, including significantly increased level of the cytokines (IFN-γ, IL-12, TNF-α and IL-10) and the activation of CD4+ and CD8+ T-lymphocytes and long term of specific antibodies against Toxoplasma. Our results strongly indicate that vaccine of WH3 Δrop18 might provide effective immune protection against a wide range strains of Toxoplasma infections and be a promising live attenuated vaccine candidate.

DOI: https://doi.org/10.1038/s41541-024-00996-9
Sci Adv. 2024 Oct 25. 10(43): eadq0101

Toxoplasma gondii macrophage migration inhibitory factor shows anti-Mycobacterium tuberculosis potential via AZIN1/STAT1 interaction.

Chanjin Yoon, Hyo Keun Kim, Yu Seong Ham, Woo Jin Gil, Seok-Jun Mun, Euni Cho, Jae-Min Yuk, Chul-Su Yang.

Mycobacterium tuberculosis (MTB) is a pathogenic bacterium, belonging to the family Mycobacteriaceae, that causes tuberculosis (TB). Toxoplasma gondii macrophage migration inhibitory factor (TgMIF), a protein homolog of macrophage migration inhibitory factor, has been explored for its potential to modulate immune responses during MTB infections. We observed that TgMIF that interacts with CD74, antizyme inhibitor 1 (AZIN1), and signal transducer and activator of transcription 1 (STAT1) modulates endocytosis, restoration of mitochondrial function, and macrophage polarization, respectively. These interactions promote therapeutic efficacy in mice infected with MTB, thereby presenting a potential route to host-directed therapy development. Furthermore, TgMIF, in combination with first-line TB drugs, significantly inhibited drug-resistant MTB strains, including multidrug-resistant TB. These results demonstrate that TgMIF is potentially a multifaceted therapeutic agent against TB, acting through immune modulation, enhancement of mitochondrial function, and dependent on STAT1 and AZIN1 pathways.

DOI: https://doi.org/10.1126/sciadv.adq0101
Drug Dev Res. 2024 Nov;85(7): e70008

Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer activities.

Busra Binarci, Ensar Korkut Kilic, Tunca Dogan, Rengul Cetin Atalay, Deniz Cansen Kahraman, Sultan Nacak Baytas.

  Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, driven mainly by chronic hepatitis infections and metabolic disorders, which highlights the urgent need for novel therapeutic strategies. Sirtuins, particularly SIRT1 are crucial in HCC pathogenesis, making it a promising drug target. Indole-based molecules show potential as therapeutic agents by interacting with key proteins like sirtuins involved in cancer progression. In this study, we designed and synthesized novel indole-based small molecules and investigated their potential sirtuin inhibitory action and anticancer activity on HCC cell lines. Four of the twenty-eight tested small molecules on different cancer types were selected (4 g, 4 h, 4o, and 7j) based on their structure-activity relationship and studied on a panel of HCC cell lines. Compounds had active drug-target interactions with SIRT1 or SIRT2 based on DEEPScreen DTI predictions and docking studies which confirmed that 4o, 4 g, and 7j were most potent in their interaction with SIRT1. Compound 4 g caused the highest sirtuin activity inhibition in vitro and induced G1 arrest and apoptosis in HCC cell lines.

Keywords:  Hepatocellular carcinoma (HCC); Sirtuins; anticancer activity; drug‐target interaction (DTI); indole‐based small molecules

DOI:  https://doi.org/10.1002/ddr.70008
mSphere. 2024 Oct 24. e0054624

The Plasmodium falciparum histone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood-stage parasites.

Matthias Wyss, Abhishek Kanyal, Igor Niederwieser, Richard Bartfai, Till S Voss.

  The malaria parasite Plasmodium falciparum employs antigenic variation of the virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copy var gene family. var genes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singular var gene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator of var gene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 in var gene regulation. We demonstrate that PfSET10 is not required for mutually exclusive var gene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulating var gene expression and is not required for blood-stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.IMPORTANCEThe malaria parasite Plasmodium falciparum infects hundreds of millions of people every year. To survive and proliferate in the human bloodstream, the parasites need to escape recognition by the host's immune system. To achieve this, P. falciparum can change the expression of surface antigens via a process called antigenic variation. This fascinating survival strategy is based on infrequent switches in the expression of single members of the var multigene family. Previous research reported conflicting results on the role of the epigenetic regulator PfSET10 in controlling mutually exclusive var gene expression and switching. Here, we unequivocally demonstrate that PfSET10 is neither required for antigenic variation nor the expression of any other proteins during blood-stage infection. This information is critical in directing our attention toward exploring alternative molecular mechanisms underlying the control of antigenic variation and investigating the function of PfSET10 in other life cycle stages.

Keywords:  CRISPR-Cas9; PfEMP1; PfSET10; Plasmodium falciparum; RNA-seq; antigenic variation; gametocytes; histone methyltransferase; malaria; var genes

DOI:  https://doi.org/10.1128/msphere.00546-24
Eur J Med Chem. 2024 Oct 17. pii: S0223-5234(24)00853-5. [Epub ahead of print]280 116972

HDAC8 as a target in drug discovery: Function, structure and design.

Qianlong Zhao, Hongyan Liu, Jie Peng, Haoqian Niu, Jingqian Liu, Haoyu Xue, Wenjia Liu, Xinyu Liu, Huabei Hao, Xinbo Zhang, Jingde Wu.

  Histone deacetylases (HDACs) have emerged as prominent therapeutic targets in drug discovery. Among the members of the HDAC family, HDAC8 exhibits distinct structural and physiological features from other members of the class Ⅰ HDACs. In addition to histones, numerous non-histone substrates such as structural maintenance of chromosomes 3 (SMC3), p53, estrogen-related receptor alpha (ERRα), etc., have been identified for HDAC8, suggesting the involvement of HDAC8 in diverse biological processes. Studies have demonstrated that HDAC8 plays essential roles in certain disease development, e.g., acute myeloid leukemia (AML), neuroblastoma, and X-Linked disorders. Despite several HDAC8 inhibitors have been discovered, only one compound has progressed to clinical studies. Recently, novel strategies targeting HDAC8 have emerged, including identifying innovative zinc-chelating groups (ZBG), developing multi-target drugs, and HDAC8 PROTACs. This review aims to summarize recent progress in developing new HDAC8 inhibitors that incorporate novel strategies and provide an overview of the clinical improvements associated with HDAC8 inhibitors.

Keywords:  Cancer; HDAC8; HDAC8 inhibitor; Histone deacetylase; Inhibitor design; PROTAC

DOI:  https://doi.org/10.1016/j.ejmech.2024.116972
Ann Med. 2024 Dec;56(1): 2418958

Histone deacetylases: potential therapeutic targets in cisplatin-induced acute kidney injury.

Shuxian Guo, Jin Zhao, Yuzhan Zhang, Yunlong Qin, Jinguo Yuan, Zixian Yu, Yan Xing, Yumeng Zhang, Yueqing Hui, Anjing Wang, Mei Han, Yueru Zhao, Xiaoxuan Ning, Shiren Sun.

  Aim: Chemotherapy has been well shown to enhance life expectancy in patients with malignancy. However, conventional chemotherapy drugs, particularly cisplatin, are highly associated with nephrotoxicity, which limits therapeutic efficacy and impairs quality of life. Histone deacetylases (HDACs) are proteases that play significant roles in diseases by influencing protein post-translational modification and gene expression. Agents that inhibit HDAC enzymes have been developed and approved by the FDA as anticancer drugs. It is worth noting that in certain preclinical studies with tumour cell lines, the integration of HDAC modulators and cisplatin not only exerts synergistic or additive tumour-killing effects but also alleviates cisplatin nephrotoxicity. The aim of this review is to discuss the role of HDACs in cisplatin nephrotoxicity.
Methods: After searching in PubMed and Web of Science databases using 'Histone deacetylase', 'nephrotoxicity', 'cisplatin', and 'onconpehrology' as keywords, studies related was compiled and examined.
Results: HDAC inhibitors exert renal protective effects by inhibiting inflammation, apoptosis, oxidative stress, and promoting autophagy; whereas sirtuins play a renal protective role by regulating lipid metabolism, inhibiting inflammation and apoptosis, and protecting mitochondrial biosynthesis and mitochondrial dynamics. These potential interactions provide clues concerning targets for molecular treatment.
Conclusion: This review encapsulates the function and molecular mechanisms of HDACs in cisplatin nephrotoxicity, providing the current view by which HDACs induce different biological signaling in the regulation of chemotherapy-associated renal injury. More importantly, this review exhaustively elucidates that HDACs could be targeted to develop a new therapeutic strategy in treating cisplatin nephrotoxicity, which will extend the knowledge of the biological impact and clinical implications of HDACs.

Keywords:  Histone deacetylase; cisplatin; nephrotoxicity; onconpehrology

DOI:  https://doi.org/10.1080/07853890.2024.2418958
FASEB J. 2024 Oct 31. 38(20): e70119

Dissecting the role of transcription factor AP2-M in Babesia asexual replication.

Jinming Wang, Yijun Chai, Jifei Yang, Yuxin Ye, Jianxun Luo, Hong Yin, Guiquan Guan.

  Babesia spp. are obligate intracellular parasites that invade host cells to complete their asexual development and transmission. Here, we identified a transcription factor AP2-M (BXIN_0799) in Babesia sp. Xinjiang (Bxj), a member of the Apicomplexan AP2 family, which regulates gene expression related to red blood cell (RBC) invasion and cell cycle progression. Our genome-wide analysis of (Cut-Tag) data shows that AP2-M specifically recognized DNA motifs in the promoters of target genes. AP2-M target genes included other AP2 gene family members and epigenetic markers, which could modulate gene expression involved in RBC invasion, merozoite morphology, and cell cycle phases, as indicated by RNA sequencing, proteomics, and single-cell RNA sequencing (scRNA-seq) data from an ap2-m gene disrupted strain (AP2-M (-)). We conclude that AP2-M appeared to contribute to the process of red blood cell invasion, maintain merozoite morphology, and cell cycle progression through GS and MS phases.

Keywords:   Babesia ; RNA sequencing; asexual development; cut‐tag; red blood cell invasion; single‐cell RNA sequencing; transcription factor

DOI:  https://doi.org/10.1096/fj.202400127RRR
J Mass Spectrom. 2024 Nov;59(11): e5095

Advancing Native Mass Spectrometry Toward Cellular Biology.

Kazumi Saikusa.

  Protein structure, including various post-translational modifications and higher-order structures, regulates diverse biological functions. Native mass spectrometry (native MS) is a powerful analytical technique used to determine the masses of biomolecules, such as proteins and their complexes, while preserving their native folding in solution. This method provides structural information on the composition of monomers or complexes and the stoichiometry of subunits within each complex, significantly contributing to protein structural analysis. Native MS has evolved to incorporate top-down approaches, enabling the characterization of proteoforms and non-covalent interactions between metabolites or proteins and specific targets. This perspective highlights the advancements in native MS for intracellular proteins and protein complexes, and discusses future research directions toward cellular biology.

Keywords:  ionization techniques; native mass spectrometry; nonvolatile salts; protein complexes; top–down proteomics

DOI:  https://doi.org/10.1002/jms.5095
J Cell Mol Med. 2024 Oct;28(20): e70120

HDAC7 promotes ovarian cancer malignancy via AKT/mTOR signalling pathway.

Qi Feng, Sheng Hao, Xiongxiu Liu, Zhong Yan, Kai Sheng, Yanping Li, Peng Zhang, Xiugui Sheng.

  Ovarian cancer is of the most lethal malignancy and causes serious threat to women health worldwide. A deep understanding of molecular mechanisms underlying ovarian cancer progression is critical for the development of promising therapeutic strategies. In this study, we aimed to employ immunohistochemistry to determine the protein level of HDAC7 in patient tissues, our data showed HDAC7 levels are upregulated in tumour tissues. In addition, we also performed Kaplan-Meier survival analysis to investigate the association between HDAC7 expression and clinical prognosis, and found that HDAC7 expression was associated with poor prognosis in ovarian cancer patients. Inhibition of HDAC7 cells resulted in lower cell proliferation, invasion and colony formation. Furthermore, we also found that HDAC7 inhibition suppressed PI3K/AKT/mTOR pathway. In contrast, exogenous HDAC7 expression activated the PI3K/AKT/mTOR pathway in HDAC7 knockout cells and rescued the cell proliferation, invasion and colony formation. However, inhibition of p-AKT induced lower cell proliferation, metastasis and colony formation abilities. In murine model, HDAC7 KO significantly decreased the tumour burden. These data indicate that HDAC7 is involved in regulation of PI3K/AKT/mTOR pathway and targeting of HDAC7 could be potential therapeutic strategy in the treatment of ovarian cancer.

Keywords:  AKT; HDAC7; histone deacetylase; mTOR; ovarian cancer

DOI:  https://doi.org/10.1111/jcmm.70120
Pathogens. 2024 Oct 02. pii: 866. [Epub ahead of print]13(10):

From Trypomastigotes to Trypomastigotes: Analyzing the One-Way Intracellular Journey of Trypanosoma cruzi by Ultrastructure Expansion Microscopy.

Ramiro Tomasina, Fabiana C González, Andrés Cabrera, Yester Basmadjián, Carlos Robello.

  The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, also called American trypanosomiasis. This neglected tropical disease affects millions of individuals across the Americas. To complete its life cycle, T. cruzi parasitizes both vertebrate hosts and its vector, commonly known as the 'kissing bug'. The parasite's survival and proliferation strategies are driven by the diverse environments it encounters. Despite being described by Carlos Chagas in 1909, significant knowledge gaps persist regarding the parasite's various life forms and adaptive capabilities in response to environmental cues. In this study, we employed Ultrastructure Expansion Microscopy to explore the intricate journey of T. cruzi within the host cell. Upon entry into the host cell, trypomastigotes undergo folding, resulting in intermediate forms characterized by a rounded cell body, anterior positioning of basal bodies, and a shortened flagellum. The repositioning of basal bodies and the kinetoplast and the shortening of the flagella mark the culmination of intracellular amastigogenesis. Furthermore, we analyzed intracellular trypomastigogenesis, identifying discrete intermediate forms, including leaf-shaped stages and epimastigote-like forms, which suggests a complex differentiation process. Notably, we did not observe any dividing intracellular epimastigotes, indicating that these may be non-replicative forms within the host cell. Our detailed examination of amastigote cell division revealed semi-closed nuclear mitosis, with mitotic spindle formation independent of basal bodies. This study provides new insights into the morphological and cytoskeletal changes during the intracellular stages of T. cruzi, providing a model for understanding the dynamics of intracellular amastigogenesis and trypomastigogenesis.

Keywords:  Trypanosoma cruzi; UExM; amastigogenesis; cell division; trypomastigogenesis

DOI:  https://doi.org/10.3390/pathogens13100866
PRX Life. 2024 Jan-Mar;2(1):pii: 013010. [Epub ahead of print]2(1):

Gene Expression Tradeoffs Determine Bacterial Survival and Adaptation to Antibiotic Stress.

Josiah C Kratz, Shiladitya Banerjee.

To optimize their fitness, cells face the crucial task of efficiently responding to various stresses. This necessitates striking a balance between conserving resources for survival and allocating resources for growth and division. The fundamental principles governing these tradeoffs is an outstanding challenge in the physics of living systems. In this study, we introduce a coarse-grained theoretical framework for bacterial physiology that establishes a connection between the physiological state of cells and their survival outcomes in dynamic environments, particularly in the context of antibiotic exposure. Predicting bacterial survival responses to varying antibiotic doses proves challenging due to the profound influence of the physiological state on critical parameters, such as the minimum inhibitory concentration (MIC) and killing rates, even within an isogenic cell population. Our proposed theoretical model bridges the gap by linking extracellular antibiotic concentration and nutrient quality to intracellular damage accumulation and gene expression. This framework allows us to predict and explain the control of cellular growth rate, death rate, MIC, and survival fraction in a wide range of time-varying environments. Surprisingly, our model reveals that cell death is rarely due to antibiotic levels being above the maximum physiological limit, but instead survival is limited by the inability to alter gene expression sufficiently quickly to transition to a less susceptible physiological state. Moreover, bacteria tend to overexpress stress response genes at the expense of reduced growth, conferring greater protection against further antibiotic exposure. This strategy is in contrast to those employed in different nutrient environments, in which bacteria allocate resources to maximize growth rate. This highlights an important tradeoff between the cellular capacity for growth and the ability to survive antibiotic exposure.

DOI: https://doi.org/10.1103/prxlife.2.013010
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Oct 18. pii: S1388-1981(24)00122-7. [Epub ahead of print]1870(1): 159572

Characterization of two Plasmodium falciparum lipid transfer proteins of the Sec14/CRAL-TRIO family.

Dominik Šťastný, Alena Balleková, Dana Tahotná, Lucia Pokorná, Roman Holič, Jana Humpolíčková, Peter Griač.

  Invasion of human red blood cells by the malaria parasite Plasmodium falciparum is followed by dramatic modifications of erythrocytes properties, including de novo formation of new membrane systems. Lipid transfer proteins from both the parasite and the host cell are most likely an important part of those membrane remodeling processes. Using bioinformatics and in silico structural analysis, we have identified five P. falciparum potential lipid transfer proteins containing cellular retinaldehyde binding - triple functional domain (CRAL-TRIO). Two of these proteins, C6KTD4, encoded by the PF3D7_0629900 gene and Q8II87, encoded by the PF3D7_1127600 gene, were studied in more detail. In vitro lipid transfer assays using recombinant C6KTD4 and Q8II87 confirmed that these proteins are indeed bona fide lipid transfer proteins. C6KTD4 transfers sterols, phosphatidylinositol 4,5 bisphosphate, and, to some degree, also phosphatidylcholine between two membrane compartments. Q8II87 possesses phosphatidylserine transfer activity in vitro. In the yeast model, the expression of P. falciparumQ8II87 protein partially complements the absence of Sec14p and its closest homologue, Sfh1p. C6KTD4 protein can substitute for the collective essential function of oxysterol-binding related proteins. According to published whole genome studies in P. falciparum, absence of C6KTD4 and Q8II87 proteins has severe consequences for parasite viability. Therefore, CRAL-TRIO lipid transfer proteins of P. falciparum are potential targets of novel antimalarials, in search for which the yeast model expressing these proteins could be a valuable tool.

Keywords:  Lipid transfer proteins; Malaria; Phospholipids; Plasmodium falciparum; Saccharomyces cerevisiae; Sterols

DOI:  https://doi.org/10.1016/j.bbalip.2024.159572
Front Cell Dev Biol. 2024 ;12 1477173

Molecular mechanisms of polarized transport to the apical plasma membrane.

Masataka Kunii, Akihiro Harada.

  Cell polarity is essential for cellular function. Directional transport within a cell is called polarized transport, and it plays an important role in cell polarity. In this review, we will introduce the molecular mechanisms of polarized transport, particularly apical transport, and its physiological importance.

Keywords:  Rab8; apical transport; cell polarity; polarized transport; unconventional transport

DOI:  https://doi.org/10.3389/fcell.2024.1477173
Neural Regen Res. 2024 Oct 22.

Exploring the role of N-acetyltransferases in diseases: a focus on N-acetyltransferase 9 in neurodegeneration.

Prajakta Deshpande, Anuradha Venkatakrishnan Chimata, Amit Singh.

ABSTRACT: Acetyltransferases, required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease. Protein acetylation is a common post-translational modification pivotal to basic cellular processes. Close to 80%-90% of proteins are acetylated during translation, which is an irreversible process that affects protein structure, function, life, and localization. In this review, we have discussed the various N-acetyltransferases present in humans, their function, and how they might play a role in diseases. Furthermore, we have focused on N-acetyltransferase 9 and its role in microtubule stability. We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases. We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00779
Eur J Cell Biol. 2024 Oct 18. pii: S0171-9335(24)00080-3. [Epub ahead of print]103(4): 151463

dCas9-HDAC8-EGFP fusion enables epigenetic editing of breast cancer cells by H3K9 deacetylation.

Mohammad Mijanur Rahman, Trygve O Tollefsbol.

  Epigenetic editing is thriving as a robust tool for manipulating transcriptional regulation and cell fate. Despite its regulatory role in gene downregulation, epigenetic editing with histone deacetylation has been sparsely studied, especially in the context of cancer. In this current study, we have reconstructed a dCas9-HDAC8-EGFP fusion to perform histone deacetylation on the promoter of the ESR1, TERT and CDKN1C genes for the first time in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in HEK293T cells. Our results demonstrated that dCas9-HDAC8-EGFP in combination with appropriate gRNAs were able to downregulate the expression of the ESR1, TERT and CDKN1C genes transcriptionally by specifically depleting the H3K9ac level on the recruitment loci. The addition of histone deacetylase inhibitors was found to neutralize the outcomes of dCas9-HDAC8-EGFP-induced epigenetic editing. Furthermore, we observed a significant downregulation of full length ERα expression in epigenetically edited MCF-7 cells with consequential alteration in cellular response toward estradiol and tamoxifen treatment due to dCas9-HDAC8-EGFP mediated epigenetic editing of the ESR1 gene. Overall, dCas9-HDAC8-EGFP is a novel circuit that enabled downregulation of crucial genes with cellular outcome in breast cancer cells by preferentially inducing H3K9 deacetylation of specific promoter regions.

Keywords:  DCas9-HDAC8-EGFP; Epigenetic editing; HDAC inhibitor; Histone deacetylation

DOI:  https://doi.org/10.1016/j.ejcb.2024.151463
mSphere. 2024 Oct 24. e0049524

The Plasmodium falciparum histone methyltransferase SET10 participates in a chromatin modulation network crucial for intraerythrocytic development.

Jean-Pierre Musabyimana, Sherihan Musa, Janice Manti, Ute Distler, Stefan Tenzer, Che Julius Ngwa, Gabriele Pradel.

  The lifecycle progression of the malaria parasite Plasmodium falciparum requires precise tuning of gene expression including histone methylation. The histone methyltransferase PfSET10 was previously described as an H3K4 methyltransferase involved in var gene regulation, making it a prominent antimalarial target. In this study, we investigated the role of PfSET10 in the blood stages of P. falciparum in more detail, using tagged PfSET10-knockout (KO) and -knockdown (KD) lines. We demonstrate a nuclear localization of PfSET10 with peak protein levels in schizonts. PfSET10 deficiency reduces intraerythrocytic growth but has no effect on gametocyte commitment and maturation. Screening of the PfSET10-KO line for histone methylation variations reveals that lack of PfSET10 renders the parasites unable to mark H3K18me1, while no reduction in the H3K4 methylation status could be observed. Comparative transcriptomic profiling of PfSET10-KO schizonts shows an upregulation of transcripts particularly encoding proteins linked to red blood cell remodeling and antigenic variation, suggesting a repressive function of the histone methylation mark. TurboID coupled with mass spectrometry further highlights an extensive nuclear PfSET10 interaction network with roles in transcriptional regulation and mRNA processing, DNA replication and repair, and chromatin remodeling. The main interactors of PfSET10 include ApiAP2 transcription factors, epigenetic regulators like PfHDAC1, chromatin modulators like PfMORC and PfISWI, mediators of RNA polymerase II, and DNA replication licensing factors. The combined data pinpoint PfSET10 as a histone methyltransferase essential for H3K18 methylation that regulates nucleic acid metabolic processes in the P. falciparum blood stages as part of a comprehensive chromatin modulation network.IMPORTANCEThe fine-tuned regulation of DNA replication and transcription is particularly crucial for the rapidly multiplying blood stages of malaria parasites and proteins involved in these processes represent important drug targets. This study demonstrates that contrary to previous reports the histone methyltransferase PfSET10 of the malaria parasite Plasmodium falciparum promotes the methylation of histone 3 at lysine K18, a histone mark to date not well understood. Deficiency of PfSET10 due to genetic knockout affects genes involved in intraerythrocytic development. Furthermore, in the nuclei of blood-stage parasites, PfSET10 interacts with various protein complexes crucial for DNA replication, remodeling, and repair, as well as for transcriptional regulation and mRNA processing. In summary, this study highlights PfSET10 as a methyltransferase affecting H3K18 methylation with critical functions in chromatin maintenance during the development of P. falciparum in red blood cells.

Keywords:  DNA replication; chromatin modulation; epigenetic gene regulation; histone methyltransferase; intraerythrocytic replication; malaria; transcription

DOI:  https://doi.org/10.1128/msphere.00495-24
Cell Stem Cell. 2024 Oct 18. pii: S1934-5909(24)00329-1. [Epub ahead of print]

Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.

Yawen Li, Yalin He, Qi Zheng, Jiazhu Zhang, Xinwen Pan, Xi Zhang, Huairui Yuan, Guangchuan Wang, Xin Liu, Xiaolong Zhou, Xueliang Zhu, Tao Ren, Pengfei Sui.

  Basal cells (BCs) are the progenitor cells responsible for tracheal epithelium integrity. Here, we demonstrate that mitochondrial pyruvate carriers (MPCs) act as metabolic checkpoints that are essential for BC fate decision. Inhibition of MPCs enables long-term expansion of BCs from both mice and humans. Genetic inactivation of Mpc2 in mice leads to BC hyperplasia and reduced ciliated cells during homeostasis, as well as delayed epithelial regeneration and accumulation of intermediate cells following injury. Mechanistically, MPC2 links glycolysis to ATP citrate lyase (ACLY)-dependent cytosolic acetyl-coenzyme A (CoA) generation, which is required for the epigenetic control of differentiation-related gene transcription. Modulating this metabolic-epigenetic axis partially rescues Yes-associated protein (YAP)-dysfunction-induced changes in BCs. Importantly, exogenous citrate promotes the differentiation of BCs from chronic obstructive lung disease (COPD) patients. Thus, beyond demonstrating the role of pyruvate metabolism in BC fate decision, our study suggests that targeting pyruvate-citrate metabolism may serve as a potential strategy to rectify abnormal BC behavior in lung diseases.

Keywords:  airway; cell fate decision; injury repair; lung basal progenitor cell; lung epithelium homeostasis; lung progenitor cell metabolism; mitochondrial pyruvate carrier

DOI:  https://doi.org/10.1016/j.stem.2024.09.015
Microb Pathog. 2024 Oct 21. pii: S0882-4010(24)00517-5. [Epub ahead of print]197 107050

Acetylation of DnaJ facilitates the proliferation of BmNPV by affecting the transport of nucleocapsids.

Jiaqi Li, Siqi Xu, Chaoguang Gu, Xinyi Fan, Xizhen Zhang, Meng Miao, Wei Yu.

  DnaJ (Orf40), a late-expressed factor of Bombyx mori nucleopolyhedrovirus (BmNPV), is essential for the budding of virions and influences the transfer of the nucleocapsid from the nucleus to the cytoplasm. Previous studies showed that the knockdown of dnaj could prevent the nucleocapsid from exiting the nucleus, but the underlying regulatory mechanism remains unknown. In our previous acetylomic analysis of BmN cells infected with wild-type BmNPV, we found that a lysine residue (K17) was acetylated 36h post-infection, and the acetylation level of this site was upregulated about 3.5-fold. Here, we found that deacetylation of DnaJ K17 significantly inhibited viral proliferation without affecting viral DNA replication. Furthermore, deacetylation of DnaJ K17 affected the interaction with two nucleocapsid-associated proteins, Ac66 and VP80, which in turn affected the production of nucleocapsids, as well as their transport within the nucleus along F-actin fibers, leading to a decrease in the export of nucleocapsids from the nucleus. The reduced amount of nucleocapsids in the cytoplasm ultimately led to a decrease in the production of budded virions and consequently inhibited viral proliferation. In conclusion, acetylation of DnaJ affects nucleocapsid production and transport, thereby influencing viral proliferation.

Keywords:  Acetylation; BmNPV; DnaJ; Nucleocapsid transport

DOI:  https://doi.org/10.1016/j.micpath.2024.107050
Mol Cells. 2024 Oct 17. pii: S1016-8478(24)00153-5. [Epub ahead of print] 100128

Effects of phospholipase D1 inhibitory peptide on the growth and metastasis of gastric cancer cells.

Dongju Kim, Mee-Sup Yoon, Junwon Lee, Shin-Young Park, Joong-Soo Han.

  Phospholipase D1 (PLD1) contributes to cancer development and progression through its effects on cell proliferation, survival, invasion, metastasis, angiogenesis, drug resistance, and modulation of the tumor microenvironment. Its central role in these processes makes it a promising target for novel cancer treatments aimed at inhibiting its activity and disrupting the signaling pathways it regulates. In this study, we aimed to investigate the effect of PLD1 inhibition on gastric cancer cell growth using a novel peptide inhibitor, TAT-TVTSP. PLD1, which plays a role in cancer progression, catalyzes the conversion of phosphatidylcholine into choline and phosphatidic acid through hydrolysis. To effectively target PLD1 in cells, we engineered TAT-TVTSP by fusing a PLD1-inhibitory peptide (TVTSP) with a cell-penetrating peptide (TAT). We observed that TAT-TVTSP effectively inhibited PLD1 activity in AGS gastric cancer cells. Moreover, TAT-TVTSP significantly inhibited the mammalian target of the rapamycin signaling pathway, including the phosphorylation of key downstream targets such as S6K1, AKT, S473, glycogen synthase kinase-3b, and forkhead box O1. TAT-TVTSP did not induce cell death, but it triggered cell cycle arrest by activating p21 and p27 via AKT phosphorylation. Functional assays revealed that TAT-TVTSP significantly impaired the colony-forming ability of AGS cells, thus inhibiting cell proliferation. Transwell and wound-healing assays revealed that this peptide disrupted the cellular behaviors critical to cancer progression, such as migration and invasion. In vivo, TAT-TVTSP significantly reduced tumor growth in the xenograft model of gastric cancer without any toxicity. Overall, our results suggest that TAT-TVTSP is a novel therapeutic agent for PLD1-mediated cancers.

Keywords:  Cell signaling cascade; Gastric cancer; Peptide inhibitor; Phospholipase D1; mTOR signaling

DOI:  https://doi.org/10.1016/j.mocell.2024.100128