bims-toxgon 2026-03-08 papers

Issue of 2026–03–08
four papers selected by
Lakesh Kumar, BITS Pilani

PLoS Negl Trop Dis. 2026 Mar;20(3): e0014052

The resistance to Toxoplasma gondii in Microtus fortis is associated with the activation of the complement lectin pathway.

Jing Xie, Mengqi Wu, Zhijun Zhou, Yuan Liu, Xiaohua Liu, Kaijuan Wu, Dongqian Yang, Yixiao Wang, Kang Liu, Chandara Ngim, Zheng Wang, Liping Jiang.

Toxoplasma gondii (T. gondii) is an intracellular parasite that infects nearly all warm-blooded animals, including humans. The susceptibility to T. gondii infection varies among hosts. In this study, we found that Microtus fortis (M. fortis) exhibited a naturally high level of resistance to the T. gondii RH strain, as evidenced by survival assays. We further observed that M. fortis activated the complement system via the lectin pathway to lyse T. gondii tachyzoites, whereas serum from Kunming (KM) mice showed no such effect. Furthermore, the ability of M. fortis to clear T. gondii tachyzoites was significantly impaired when the complement system was inhibited by cobra venom factor (CVF). These findings indicate that M. fortis exhibits a naturally high resistance to T. gondii. This resistance is mediated, in part, by the complement system, which is activated through the lectin pathway and directly lyses extracellular tachyzoites. Thus, the complement system plays an essential role in controlling T. gondii infection in this species.

DOI: https://doi.org/10.1371/journal.pntd.0014052

J Cell Sci. 2026 Mar 01. pii: jcs264310. [Epub ahead of print]139(5):

Unconventional model organisms bend our view on mitochondrial cristae.

Silvia Tassan-Lugrezin, Silje A C A Debets, Laura van Niftrik, Taco W A Kooij, Irina Bregy.

Cristae, convolutions of the inner mitochondrial membrane, provide an extended surface area for respiratory chain complexes and ATP synthases. Crista structure has been extensively researched in opisthokont model organisms, such as yeast and various animals; however, the vast majority of eukaryotic cristae diversity has been largely unexplored. Here, we provide a comprehensive overview of crista formation and maintenance in Euglenozoa and Alveolata, two highly divergent eukaryotic clades that include parasites of clinical and veterinary importance. Within these clades, cristae have been studied primarily in the kinetoplastid Trypanosoma brucei and the apicomplexan Toxoplasma gondii. We also discuss the apicomplexan Plasmodium falciparum, the deadliest human parasite and etiological agent of malaria, in which de novo formation of cristae occurs naturally following an apparently acristate life cycle stage. We compare findings from these divergent and disease-relevant organisms with those from more traditional model organisms, highlighting conserved and unique traits across the eukaryotic kingdom. In this Review, we focus on the roles of three key players in crista curvature - ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS) and cardiolipin, a lipid specific to the inner mitochondrial membrane. By comparing distantly related organisms, we synthesize a broadly applicable model of the general principles of crista formation.

Keywords: Plasmodium falciparum ; Toxoplasma gondii ; Trypanosoma brucei ; ATP synthase; Apicomplexa; Cardiolipin; Kinetoplastida; MICOS; Mitochondrial cristae

DOI: https://doi.org/10.1242/jcs.264310

Eur J Pharmacol. 2026 Mar 03. pii: S0014-2999(26)00203-7. [Epub ahead of print] 178721

Bridging Protein Quality Control and Epigenetic Dysregulation: The HDAC6 Paradox in Neurological Disorders and Therapeutic Targeting.

Yuhan Chen, Yutong Wu, Xiong Liu, Jiali Wan, Mi Shen, Qi Zhang.

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics.

Keywords: HDAC6 inhibitors; acetylation; histone deacetylase 6 (HDAC6); neurodegenerative diseases; peripheral neuropathy

DOI: https://doi.org/10.1016/j.ejphar.2026.178721

Methods Enzymol. 2026 ;pii: S0076-6879(25)00525-7. [Epub ahead of print]727 47-74

Docking and molecular dynamics simulations of ORPphilins targeting OSBP.

Zoé Grimanelli, Bruno Mesmin, Romain Gautier.

Oxysterol-bind protein (OSBP) mediates cholesterol/phosphatidylinositol-4-phosphate (PI4P) exchange between subcellular compartments, thereby contributing to numerous cellular processes and being linked to several diseases such as cancer and viral infections. Its lipid transfer activity relies on the ORD domain, which forms a hydrophobic pocket enabling binding of sterols and PI4P. Natural compounds from the ORPphilin family have emerged as promising antiviral agents, by targeting the OSBP ORD. However, their functioning at the molecular level remains poorly documented. In this chapter, we detail molecular modelling approaches that offer a valuable tool for exploring these interactions, as they provide dynamic insights into proteinligand complexes not captured by crystallography alone, while being much faster to obtain. With docking and molecular dynamics (MD) simulations methods, one can predict ORPphilin orientations within the ORD pocket, visualize the complexes, and identify specific binding residues, which could serve as basis for designing mutagenesis experiments. MD simulations can further reveal differences in binding energies among ORPphilins, thereby providing mechanistic insights and rationalization of experimental observations.

Keywords: Antiviral compounds; Docking; Lipid-transfer protein; MD simulations; OSBP

DOI: https://doi.org/10.1016/bs.mie.2025.11.021