bims-toxgon 2025-04-06 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–04–06
27 papers selected by
Lakesh Kumar, BITS Pilani

Phosphatase UBLCP1 is required for the growth, virulence and mitochondrial integrity of Toxoplasma gondii.
Metabolic adaptability and nutrient scavenging in Toxoplasma gondii: insights from ingestion pathway-deficient mutants.
Novel Drug Targets for the Bradyzoite Form of Toxoplasma gondii.
Toxoplasma induced cytokine release syndrome is critically dependent on the expression of pore-forming Perforin-Like Protein-1.
Crosstalk between metabolism and epigenetics during macrophage polarization.
A Conditional Cas9 System for Stage-Specific Gene Editing in P. falciparum.
PfGCN5 is essential for Plasmodium falciparum survival and transmission and regulates Pf H2B.Z acetylation and chromatin structure.
NAD_MCNN: Combining Protein Language Models and Multiwindow Convolutional Neural Networks for Deacetylase NAD+ Binding Site Prediction.
A dynamin-like protein in Plasmodium falciparum plays an essential role in parasite growth, mitochondrial development and homeostasis during asexual blood stages.
Histone acetylation modulators in breast cancer.
Temporal and spatial distribution of histone acetylation in mouse molar development.
SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host Salmonella pH Balance during Infection.
Generation of inositol polyphosphates through a phospholipase C-independent pathway involving carbohydrate and sphingolipid metabolism in Trypanosoma cruzi.
SIRT7-mediated NRF2 deacetylation promotes antioxidant response and protects against chemodrug-induced liver injury.
VAPA mediates lipid exchange between Leishmania amazonensis and host macrophages.
Parasite and vector circadian clocks mediate efficient malaria transmission.
Leveraging AI to Explore Structural Contexts of Post-Translational Modifications in Drug Binding.
Functions and mechanisms of non-histone post-translational modifications in cancer progression.
14-3-3ε UFMylation promotes RIG-I-mediated signaling.
Filling in missing puzzle pieces in protein structural biology with cross-linking mass spectrometry.
Correction to "Rewiring the Vehicle: Trypanosoma cruzi Parasites Alter the Antennae of Their Triatomine Hosts".
Metagenomic detection of protozoan parasites on leafy greens aided by a rapid and efficient DNA extraction protocol.
A dual reporter system for intracellular and extracellular amino acid sensing in budding yeast.
Two E-clade Protein Phosphatase 2Cs enhance ABA signaling by dephosphorylating ABI1 in Arabidopsis.
[Research progress in energy metabolism design of cell factories].
Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation.
Histone Deacetylase 6 (HDAC6) in Ciliopathies: Emerging Insights and Therapeutic Implications.

Parasit Vectors. 2025 Mar 28. 18(1): 122

Phosphatase UBLCP1 is required for the growth, virulence and mitochondrial integrity of Toxoplasma gondii.

Kaiyin Sheng, Kaiyue Song, Yimin Yang, Haiyan Wu, Zhendong Du, Xueqiu Chen, Yi Yang, Guangxu Ma, Aifang Du.

   BACKGROUND: The mitochondrion is proposed as an ideal target organelle for the control of apicomplexan parasites, whose integrity depends on well-controlled protein import, folding, and turnover. The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) was found to be associated with the mitochondrial integrity in Toxoplasma gondii. However, little is known about the roles and mechanisms of UBLCP1 in this apicomplexan parasite.
METHODS: The subcellular localization of UBLCP1 in the tachyzoites of T. gondii was determined by an indirect immunofluorescence assay. The roles of UBLCP1 in the growth, cell cycle, and division of T. gondii were assessed by knocking out this molecule in the tachyzoites. Comparative phosphoproteomics between the UBLCP1-deficient and wild-type tachyzoites were performed to understand the roles of UBLCP1 in T. gondii. The virulence of UBLCP1-deficient tachyzoites of T. gondii was tested in mice.
RESULTS: UBLCP1 is expressed in the nucleus and cytoplasm of T. gondii tachyzoites. Tachyzoites lacking UBLCP1 exhibit collapsed mitochondrion, decreased mitochondrial membrane potential, and compromised growth and proliferation in vitro. Proteins involved in protein turnover and intracellular trafficking have been found differentially phosphorylated in the UBLCP1-deficient tachyzoites compared with the control. Deletion of UBLCP1 also shows that this phosphatase is essential for the propagation and virulence of T. gondii tachyzoites. Mice immunized with UBLCP1-deficient T. gondii tachyzoites survived challenges with the virulent PRU or VEG strain.
CONCLUSIONS: UBLCP1 is required for the mitochondrial integrity and essential in the lytic cycle (e.g., host cell invasion and parasite replication) in vitro and the pathogenicity of this parasite in vivo. UBLCP1 is a candidate target for a vaccine or a drug for toxoplasmosis in animals.

Keywords:   Toxoplasma gondii ; Mitochondrial integrity; Pathogenicity; UBLCP1; Vaccine candidate

DOI:  https://doi.org/10.1186/s13071-025-06766-3
mSphere. 2025 Apr 02. e0101124

Metabolic adaptability and nutrient scavenging in Toxoplasma gondii: insights from ingestion pathway-deficient mutants.

Patrick A Rimple, Einar B Olafsson, Benedikt M Markus, Fengrong Wang, Leonardo Augusto, Sebastian Lourido, Vern B Carruthers.

  The obligate intracellular parasite Toxoplasma gondii replicates within a specialized compartment called the parasitophorous vacuole (PV). Recent work showed that despite living within a PV, Toxoplasma endocytoses proteins from the cytosol of infected host cells via a so-called ingestion pathway. The ingestion pathway is initiated by dense granule protein GRA14, which binds host endosomal sorting complex required for transport (ESCRT) machinery to bud vesicles into the lumen of the PV. The protein-containing vesicles are internalized by the parasite and trafficked to the plant vacuole-like compartment (PLVAC), where cathepsin protease L (CPL) degrades the cargo, and the chloroquine resistance transporter (CRT) exports the resulting peptides and amino acids to the parasite cytosol. However, although the ingestion pathway was proposed to be a conduit for nutrients, there is limited evidence for this hypothesis. We reasoned that if Toxoplasma uses the ingestion pathway to acquire nutrients, then parasites lacking GRA14, CPL, or CRT should rely more on biosynthetic pathways or alternative scavenging pathways. To explore this, we conducted a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen in wild-type (WT) parasites and Δgra14, Δcpl, and Δcrt mutants to identify genes that become more fitness conferring in ingestion-deficient parasites. Our screen revealed a significant overlap of genes that potentially become more fitness conferring in the ingestion mutants compared to WT. Pathway analysis indicated that Δcpl and Δcrt mutants relied more on pyrimidine biosynthesis, fatty acid biosynthesis, tricarboxylic acid (TCA) cycle, and lysine degradation. Bulk metabolomic analysis showed reduced levels of glycolytic intermediates and amino acids in the ingestion mutants compared to WT, highlighting the pathway's potential role in host resource scavenging. Interestingly, Δcpl and Δcrt showed an exacerbated growth defect when cultured in amino acid-depleted media, suggesting that disrupting proteolysis or the export of proteolytic products from the PLVAC affects parasite survival during nutrient scarcity.
IMPORTANCE: Toxoplasma gondii is an obligate intracellular pathogen that infects virtually any nucleated cell in most warm-blooded animals. Infections are asymptomatic in most cases, but people with weakened immunity can experience severe disease. For the parasite to replicate within the host, it must efficiently acquire essential nutrients, especially as it is unable to make several key metabolites. Understanding the mechanisms by which Toxoplasma scavenges nutrients from the host is crucial for identifying potential therapeutic targets. Our study suggests that the ingestion pathway contributes to sustaining parasite metabolites and parasite replication under amino acid-limiting conditions. This work advances our understanding of the metabolic adaptability of Toxoplasma.

Keywords:  CRISPR; Toxoplasma gondii; amino acids; metabolism

DOI:  https://doi.org/10.1128/msphere.01011-24
Res Rep Trop Med. 2025 ;16 25-30

Novel Drug Targets for the Bradyzoite Form of Toxoplasma gondii.

Justin Orlando Ortiz, Anna K Potter, Imaan Benmerzouga.

  Toxoplasma gondii is a world-wide parasite, with an estimated prevalence of approximately 30%. Toxoplasmosis is a severe disease in the immunocompromised, but few symptoms are exhibited by patients with an intact immune system, making this parasite a worldwide burden. Currently, few drugs exist in treating acute toxoplasmosis and no drugs exist to eliminate the bradyzoite of T. gondii. Effective therapies against acute and chronic toxoplasmosis are urgently needed to reduce the burden of this disease. This review aims to give a summary of recent findings in the bradyzoite form of Toxoplasma gondii and the implication of these findings on drug development. A thorough search of PubMed and Google Scholar databases was used to identify studies within the past 10 years that illustrate targetable key elements in the differentiation and formation of the bradyzoite form of T. gondii.

Keywords:  Toxoplasma gondii; anti-toxoplasma agents; bradyzoite; chronic toxoplasmosis; toxoplasmosis

DOI:  https://doi.org/10.2147/RRTM.S431290
bioRxiv. 2025 Mar 17. pii: 2025.03.17.643671. [Epub ahead of print]

Toxoplasma induced cytokine release syndrome is critically dependent on the expression of pore-forming Perforin-Like Protein-1.

Beth Gregg, Alfredo J Guerra, Stephen A Raverty, Aline Sardinha-Silva, Bjorn F C Kafsack, Tracey L Schultz, Stephen J Gurczynski, Bethany B Moore, Vern B Carruthers, Michael E Grigg.

Acute virulence in Toxoplasma gondii is linked to an excessive proinflammatory cytokine cascade during laboratory murine infection. Previous work showed that T. gondii secretes a pore forming protein, PLP1, that is required for efficient cytolytic egress from host cells. Deletion of the PLP1 gene results in defective egress from infected culture cells and a marked reduction in parasite virulence. The goal of the present study was to gain insight into the nature of the attenuated virulence observed in PLP1 knockout compared to wild type (WT) RH parasites. Using in vivo bioluminescence imaging, we show that parasites lacking PLP1 establish an acute infection and disseminate throughout the infected mice. Histological tissue analysis indicates that parasites cause severe pathology, even in the absence of PLP1. However, mice infected with Δplp1 parasites evoke a protective inflammatory response, demonstrated by mouse survival and control of infection. Flow cytometric analysis was used to determine cellular changes occurring during both WT and Δ plp1 parasite infection. Parasite control in the Δplp1 infection was associated with earlier activation of myeloid cells and a moderate neutrophil response that, by comparison, becomes the dominant infiltrating cell type of WT infection. Positive disease outcome during Δplp1 parasite infection is also associated with regulated induction of proinflammatory cytokines, including IFN-γ and TNF-α, and an earlier IL-10 regulatory response that is dysregulated during WT infection. Together these findings suggest a key role for Toxoplasma PLP1 in promoting a lethal inflammatory immune response during acute infection with a virulent strain of the parasite.
Author Summary: Pore-forming proteins are virulence determinants expressed by multiple different pathogens, with varied roles including cellular invasion and escape, immune cell destruction, and the hijack of host cell defenses. The pathogen, Toxoplasma gondii , expresses a pore-forming protein PLP1, that is required for cell lysis and acute virulence in mice. Here, we investigate the potential mechanisms by which this pore-forming protein promotes parasite virulence; from parasite replication and dissemination to immunologic outcomes after infection. In vivo infections demonstrate that parasites replicate, disseminate, and stimulate a protective immune response when PLP1 is not expressed. We show that PLP1 expression induces a parasite driven dysregulation of cell populations and cytokine/chemokine responses, resulting in cytokine release syndrome. In a broader context, Toxoplasma's PLP1 is comparable to other pathogen pore-forming proteins that function as virulence determinants by their ability to alter host immune responses.

DOI: https://doi.org/10.1101/2025.03.17.643671
Epigenetics Chromatin. 2025 Mar 29. 18(1): 16

Crosstalk between metabolism and epigenetics during macrophage polarization.

Kangling Zhang, Chinnaswamy Jagannath.

  Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Keywords:  Acetylation; Epigenetics; Glucose metabolism; Histones; IFN-γ; IL-13; IL-4; IL10; M1; M2; Macrophage polarization; Macrophages; Metabolism; Methylation; Sirtuins

DOI:  https://doi.org/10.1186/s13072-025-00575-9
bioRxiv. 2025 Mar 10. pii: 2025.03.09.642268. [Epub ahead of print]

A Conditional Cas9 System for Stage-Specific Gene Editing in P. falciparum.

Sean T Windle, Maxwell L Neal, Fred D Mast, Stefan H I Kappe, John D Aitchison.

The malaria parasite has a complex lifecycle involving various host cell environments in both human and mosquito hosts. The parasite must tightly regulate gene expression at each stage in order to adapt to its current environment while continuing development. However, it is challenging to study gene function and regulation of essential genes across the parasite's multi-host lifecycle. Thus, we adapted a recently developed a single-plasmid dimerizable Cre recombinase system for rapamycin-controllable expression of Cas9, allowing for conditional introduction of mutations. We explored rates of gene deletion using varying repair template lengths, showing functionality of donor templates under 250bp for homology-directed repair. As a proof of concept, we conditionally disrupted two uncharacterized genes in blood and gametocyte stages, identifying new stage-specific phenotypes.
Importance: As progress towards eliminating malaria has stalled, there is a pressing need for new antimalarials and vaccines. Genes essential to multiple stages of development represent ideal candidates for both antimalarials and vaccines. However, much of the parasite genome remains uncharacterized. Conditional gene perturbation approaches are needed in order to study gene function across the lifecycle. Currently available tools are limited in their ability to perturb genes at the scale required for large screens. We describe a tool that allows for conditional introduction of desired mutations by controlling Cas9 with the DiCre-loxP system. We demonstrate the accessibility of this approach by designing gRNA-donor pairs that can be commercially synthesized. This toolkit provides a scalable system for identifying new drug and vaccine candidates targeting multiple stages of the parasite lifecycle.

DOI: https://doi.org/10.1101/2025.03.09.642268
Nucleic Acids Res. 2025 Mar 20. pii: gkaf218. [Epub ahead of print]53(6):

PfGCN5 is essential for Plasmodium falciparum survival and transmission and regulates Pf H2B.Z acetylation and chromatin structure.

Jingyi Tang, Lee M Yeoh, Myriam D Grotz, Christopher D Goodman, Jingyi Tang, Hanh H T Nguyen, Chunhao Yu, Kapil Pareek, Fairley McPherson, Anton Cozijnsen, Samuel A Hustadt, Gabrielle A Josling, Karen P Day, Danae Schulz, Geoffrey I McFadden, Tania F de Koning-Ward, Michaela Petter, Michael F Duffy.

Plasmodium falciparum causes most malaria deaths. Its developmental transitions and environmental adaptation are partially regulated by epigenetic mechanisms. Plasmodium falciparum GCN5 (PfGCN5) is an epigenetic regulator that acetylates lysines and can also bind to acetylated lysine residues on histones via its bromodomain (BRD). Here, we showed that PfGCN5 was essential for parasite transmission and survival in human blood and mosquitoes. PfGCN5 regulated genes important for metabolism and development and its BRD was required at euchromatic gene promoters for their proper expression and for acetylation of the variant histone Pf H2B.Z. However, PfGCN5 was most abundant in heterochromatin and loss of the PfGCN5 BRD de-repressed heterochromatic genes and increased levels of acetylated Pf H2B.Z in heterochromatin. The PfGCN5 BRD-binding compound L-45 phenocopied deletion of the PfGCN5 BRD, identifying PfGCN5 as a promising drug target for BRD inhibitors. Thus, PfGCN5 appears to directly contribute to activating euchromatic promoters, but PfGCN5 is also critical for maintaining repressive heterochromatin structure.

DOI: https://doi.org/10.1093/nar/gkaf218
Chem Biol Drug Des. 2025 Apr;105(4): e70085

NAD_MCNN: Combining Protein Language Models and Multiwindow Convolutional Neural Networks for Deacetylase NAD+ Binding Site Prediction.

Van-The Le, Yu-Chen Liu, Yan-Yun Chang, Yu-Cheng Lee, Yi-Jing Lin, Muhammad-Shahid Malik, Yu-Yen Ou.

  Sirtuins, a class of NAD+ -dependent deacetylases, play a key role in aging, metabolism, and longevity. Their interaction with NAD+ at the catalytic site is crucial for function, but experimental methods to map NAD+ binding sites are time consuming. To address this, we developed a computational method integrating pretrained protein language models with multiwindow convolutional neural networks (CNNs). This method captures sequence information and diverse local patterns, achieving state-of-the-art performance, with AUC of 0.9733 for human sirtuin proteins and 0.9701 for other NAD-dependent deacylation enzymes. These findings offer insights into the role of sirtuins in aging and their broader biological functions while providing a new path for identifying therapeutic targets in aging-related diseases.

Keywords:  NAD‐dependent deacetylation proteins; convolutional neural networks; multiple windows scanning; pretrained language model; sirtuins

DOI:  https://doi.org/10.1111/cbdd.70085
Biochim Biophys Acta Mol Cell Res. 2025 Mar 27. pii: S0167-4889(25)00045-X. [Epub ahead of print] 119940

A dynamin-like protein in Plasmodium falciparum plays an essential role in parasite growth, mitochondrial development and homeostasis during asexual blood stages.

Vandana Thakur, Md Muzahidul Islam, Shweta Singh, Sumit Rathore, Azhar Muneer, Gaurav Dutta, Mudassir M Banday, Priya Arora, Mohammad E Hossain, Shaifali Jain, Shakir Ali, Asif Mohmmed.

  Malaria parasites harbour a single mitochondrion, and its proper segregation during parasite multiplication is crucial for the propagation of the parasite within the host. Mitochondrial division machinery consists of several proteins that associate with the mitochondrial membrane during segregation. Here, we have identified a dynamin-like protein in P. falciparum, PfDyn2, and deciphered its role in mitochondrial growth and homeostasis. A GFP targeting approach combined with high-resolution microscopy studies showed that the PfDyn2 associates with the mitochondrial membrane at specific sites during mitochondrial division. The C-terminal degradation tag mediated inducible knock-down (iKD) of PfDyn2 significantly inhibited parasite growth. PfDyn2-iKD hindered mitochondrial development and functioning, decreased mtDNA replication, and induced mitochondrial oxidative stress, ultimately causing parasite death. Regulated overexpression of a phosphorylation mutant of PfDyn2 (Ser-612-Ala) did not affect the recruitment of PfDyn2 on the mitochondria; normal mitochondrial division and parasite growth showed that phosphorylation/dephosphorylation of this conserved serine residue (Ser612) may not be responsible for regulating recruitment of PfDyn2 to the mitochondrion. Overall, we show the essential role of PfDyn2 in mitochondrial development and maintaining its homeostasis during the asexual cycle of the parasite.

Keywords:  Dynamin; Dynamin-like protein (DLPs); Malaria; Mitochondrial development; Mitochondrial homeostasis; Plasmodium

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119940
Breast Cancer Res. 2025 Mar 31. 27(1): 49

Histone acetylation modulators in breast cancer.

Xueying Yuan, Jeffrey M Rosen.

  Breast cancer is the most prevalent cancer in women worldwide. Aberrant epigenetic reprogramming such as dysregulation of histone acetylation has been associated with the development of breast cancer. Histone acetylation modulators have been targeted as potential treatments for breast cancer. This review comprehensively discusses the roles of these modulators and the effects of their inhibitors on breast cancer. In addition, epigenetic reprogramming not only affects breast cancer cells but also the immunosuppressive myeloid cells, which can facilitate breast cancer progression. Therefore, the review also highlights the roles of these immunosuppressive myeloid cells and summarizes how histone acetylation modulators affect their functions and phenotypes. This review provides insights into histone acetylation modulators as potential therapeutic targets for breast cancer.

Keywords:  Epigenetics; Histone acetylation; Myeloid cells

DOI:  https://doi.org/10.1186/s13058-025-02006-9
PeerJ. 2025 ;13 e19215

Temporal and spatial distribution of histone acetylation in mouse molar development.

Wen Du, Wanyi Luo, Liwei Zheng, Xuedong Zhou, Wei Du.

  Histone acetylation is one of the most widely studied histone modification, regulating a variety of biological activities like organ development and tumorigenesis. However, the role of histone acetylation in tooth development is poorly understood. Using the mouse molar as a model, we mapped the distribution patterns of histone H3 and H4, as well as their corresponding acetylation sites during tooth formation in order to unveil the connection between histone acetylation modification and tooth development. Moreover, key histone acetyltransferases and histone deacetylases were detected in both epithelial and mesenchymal cells during tooth development by scRNA-seq and immunohistochemistry. These results suggest that histone acetylation modification functions as an important mechanism in tooth development at different stages.

Keywords:  Epigenetic modification; Histone acetylation; Molar development; Tooth

DOI:  https://doi.org/10.7717/peerj.19215
ACS Infect Dis. 2025 Apr 01.

SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host Salmonella pH Balance during Infection.

Dipasree Hajra, Vikas Yadav, Amit Singh, Dipshikha Chakravortty.

  Mitochondria are important organelles that regulate energy homeostasis. Mitochondrial health and dynamics are crucial determinants of the outcome of several bacterial infections. SIRT3, a major mitochondrial sirtuin, along with SIRT1 regulates key mitochondrial functions. This led to considerable interest in understanding the role of SIRT1 and SIRT3 in governing mitochondrial functions during Salmonella infection. Here, we show that loss of SIRT1 and SIRT3 function either by shRNA-mediated knockdown or by inhibitor treatment led to increased mitochondrial dysfunction with alteration in mitochondrial bioenergetics alongside increased mitochondrial superoxide generation in Salmonella-infected macrophages. Consistent with dysfunctional mitochondria, mitophagy was induced along with altered mitochondrial fusion-fission dynamics in S. typhimurium-infected macrophages. Additionally, the mitochondrial bioenergetic alteration promotes acidification of the infected macrophage cytosolic pH. This host cytosolic pH imbalance skewed the intraphagosomal and intrabacterial pH in the absence of SIRT1 and SIRT3, resulting in decreased SPI-2 gene expression. Our results suggest a novel role for SIRT1 and SIRT3 in maintaining the intracellular Salmonella niche by modulating the mitochondrial bioenergetics and dynamics in the infected macrophages.

Keywords:  SPI-2 secretion; Salmonella; fusion-fission dynamics; macrophage-bacterial pH regulation; mitochondrial bioenergetics; mitophagy

DOI:  https://doi.org/10.1021/acsinfecdis.4c00751
mBio. 2025 Apr 02. e0331824

Generation of inositol polyphosphates through a phospholipase C-independent pathway involving carbohydrate and sphingolipid metabolism in Trypanosoma cruzi.

Mayara S Bertolini, Sabrina E Cline, Miguel A Chiurillo, Brian S Mantilla, Aharon Eidex, Logan P Crowe, Danye Qiu, Henning J Jessen, Adolfo Saiardi, Roberto Docampo.

  Inositol phosphates are involved in a myriad of biological roles and activities such as Ca2+ signaling, phosphate homeostasis, energy metabolism, and disease pathogenicity. In Saccharomyces cerevisiae, synthesis of inositol phosphates occurs through the phosphoinositide phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol and further IP3 phosphorylation by additional kinases that leads to the formation of highly phosphorylated inositol derivatives, known as inositol pyrophosphates. Inositol-tetrakisphosphate 1-kinase (ITPK1) is an enzyme that mediates a PLC-independent inositol polyphosphate synthesis through phosphorylation of inositol monophosphates and other intermediates in the cytosol. In this work, we identified and characterized a Trypanosoma cruzi ITPK1 (TcITPK1) homolog. The ability of TcITPK1 to act as the mediator for this alternative pathway was established through plc1Δ and plc1Δ isc1Δ yeast complementation assays and SAX-HPLC analyses of radioactively labeled inositol. TcITPK1 localizes to the cytosol, and knockout attempts of TcITPK1 revealed that only one allele was replaced by the DNA donor cassette at the specific locus, suggesting that null alleles may have lethal effects in epimastigotes. Ablation of T. cruzi phosphoinositide phospholipase C 1 (TcPI-PLC1) affected the synthesis of IP3 from glucose 6-phosphate but did not affect the synthesis of inositol polyphosphates, while ablation of inositol phosphosphingolipid phospholipase (TcISC1) affected the synthesis of inositol polyphosphates, thus revealing that the PLC-independent pathway using either glucose 6-phosphate or inositol phosphoceramide is involved in the synthesis of inositol polyphosphates, while the PLC-dependent pathway is involved in IP3 formation needed for Ca2+ signaling.
IMPORTANCE: Millions of people are infected with Trypanosoma cruzi, and the current treatment is not satisfactory. Inositol pyrophosphates have been established as important signaling molecules. Our work demonstrates the presence of a phospholipase C-independent pathway for the synthesis of inositol pyrophosphates in T. cruzi. Furthermore, we demonstrate that this pathway starts with the synthesis of inositol monophosphates from glucose 6-phosphate or from inositol phosphoceramide, linking it to carbohydrate and sphingolipid metabolism. The essentiality of the pathway for the survival of T. cruzi infective stages makes it an ideal drug target for treating American trypanosomiasis.

Keywords:  Trypanosoma cruzi; inositol phosphoceramide; inositol pyrophosphates; phospholipase C; sphingolipids

DOI:  https://doi.org/10.1128/mbio.03318-24
Cell Death Dis. 2025 Apr 01. 16(1): 232

SIRT7-mediated NRF2 deacetylation promotes antioxidant response and protects against chemodrug-induced liver injury.

Tingzi Yu, Cong Ding, Jinying Peng, Gaoshuang Liang, Yongyi Tang, Jinqiu Zhao, Zhuan Li.

NRF2 has been recognized as a central hub that neutralizes ROS and restores intracellular redox balance. In addition to KEAP1 mediated ubiquitin-proteasome degradation, post-translational modifications of NRF2 are critical for regulating its nuclear translocation and activation but precise mechanisms underly this regulation remain elusive. In this study, we found that SIRT7 was sufficient and essential for NRF2 nuclear localization and activation. Knockdown of SIRT7 significantly impaired intercellular ROS homeostasis and increased apoptosis in response to oxidative stress including chemodrug treatment. SIRT7 interacted with NRF2 and induced its deacetylation, by which inhibited binding of NRF2 to KEAP1, enhanced NRF2 protein stability and promoted its nuclear translocation. SIRT7 induced NRF2 deacetylation at K443 and K518 sites. Lysine-arginine mutations of these sites (2KR NRF2) significantly reduced KEAP1/NRF2 binding, increased NRF2 nuclear translocation and target gene expression, decreased intercellular ROS level, whereas lysine-glutamine (2KQ) mutant showed similar subcellular localization and functions with WT. Knockdown SIRT7 in hepatocyte exacerbated Oxaliplatin (Oxa) induced hepatic injury and inflammation. While AAV8-NRF2-mediated hepatic NRF2 overexpression or NRF2 agonist significantly prevented Oxa-induced elevation of ALT levels, sinusoidal dilatation and inflammation in SIRT7HKO mice. Our data thus uncovered previously unidentified role of SIRT7 in modulating NRF2 nuclear localization and activation via deacetylation. Activating SIRT7 might offer protection against chemodrug-induced liver injury.

DOI: https://doi.org/10.1038/s41419-025-07549-5
PLoS Pathog. 2025 Mar 31. 21(3): e1012636

VAPA mediates lipid exchange between Leishmania amazonensis and host macrophages.

Ilona Gdovinova, Albert Descoteaux.

Leishmania is a vacuolar pathogen that replicates within parasitophorous vacuoles inside host phagocytes. To promote its replication, Leishmania relies on a panoply of strategies to acquire macromolecules such as lipids from host macrophages. In this study, we have evaluated the role of VAPA, an endoplasmic reticulum-resident membrane protein involved in inter-organellar lipid transport, in macrophages infected with L. amazonensis. Following infection of bone marrow-derived macrophages with metacyclic L. amazonensis promastigotes, we observed that VAPA gradually associates with communal parasitophorous vacuoles. Knockdown of VAPA prevented the replication of L. amazonensis, which was accompanied by an impaired parasitophorous vacuole expansion. Using fluorescent ceramide, we established that VAPA is required for the transport of sphingolipids to the parasitophorous vacuoles and for its acquisition by L. amazonensis amastigotes. Proximity-ligation assays revealed that L. amazonensis hijacks VAPA by disrupting its interactions with the host cell lipid transfer proteins CERT and ORP1L. Finally, we found that VAPA is essential for the transfer of the Leishmania virulence glycolipid lipophosphoglycan from the parasitophorous vacuoles to the host cell endoplasmic reticulum. We propose that VAPA contributes to the ability of L. amazonensis to colonize macrophages by mediating bi-directional transfer of lipids essential for parasite replication and virulence between the parasitophorous vacuoles and the host cell endoplasmic reticulum.

DOI: https://doi.org/10.1371/journal.ppat.1012636
Nat Microbiol. 2025 Apr;10(4): 882-896

Parasite and vector circadian clocks mediate efficient malaria transmission.

Inês Bento, Brianna A Parrington, Rushlenne Pascual, Alexander S Goldberg, Eileen Wang, Hani Liu, Helene Borrmann, Mira Zelle, Nicholas Coburn, Joseph S Takahashi, Joshua E Elias, Maria M Mota, Filipa Rijo-Ferreira.

Malaria transmission begins when Anopheles mosquitos deposit saliva and Plasmodium parasites during a bloodmeal. As Anopheles mosquitos are nocturnal, we investigated whether their salivary glands are under circadian control, anticipating bloodmeals and modulating parasite biology for host encounters. Here we show that approximately half of the mosquito salivary gland transcriptome, particularly genes essential for efficient bloodmeals such as anti-blood clotting factors, exhibits circadian expression. Furthermore, measuring haemoglobin levels, we demonstrate that mosquitos prefer to feed and ingest more blood at nighttime. Notably, we show a substantial subset of the salivary-gland-resident parasite transcriptome cycling throughout the day, indicating that this stage is not transcriptionally quiescent. Among the sporozoite genes undergoing rhythmic expression are those involved in parasite motility, potentially modulating the ability to initiate infection at different times of day. Our findings suggest a circadian tripartite relationship between the vector, parasite and mammalian host that together modulates malaria transmission.

DOI: https://doi.org/10.1038/s41564-025-01949-1
bioRxiv. 2025 Mar 20. pii: 2025.01.14.633078. [Epub ahead of print]

Leveraging AI to Explore Structural Contexts of Post-Translational Modifications in Drug Binding.

Kirill E Medvedev, R Dustin Schaeffer, Nick V Grishin.

  Post-translational modifications (PTMs) play a crucial role in allowing cells to expand the functionality of their proteins and adaptively regulate their signaling pathways. Defects in PTMs have been linked to numerous developmental disorders and human diseases, including cancer, diabetes, heart, neurodegenerative and metabolic diseases. PTMs are important targets in drug discovery, as they can significantly influence various aspects of drug interactions including binding affinity. The structural consequences of PTMs, such as phosphorylation-induced conformational changes or their effects on ligand binding affinity, have historically been challenging to study on a large scale, primarily due to reliance on experimental methods. Recent advancements in computational power and artificial intelligence, particularly in deep learning algorithms and protein structure prediction tools like AlphaFold3, have opened new possibilities for exploring the structural context of interactions between PTMs and drugs. These AI-driven methods enable accurate modeling of protein structures including prediction of PTM-modified regions and simulation of ligand-binding dynamics on a large scale. In this work, we identified small molecule binding-associated PTMs that can influence drug binding across all human proteins listed as small molecule targets in the DrugDomain database, which we developed recently. 6,131 identified PTMs were mapped to structural domains from Evolutionary Classification of Protein Domains (ECOD) database. Scientific contribution. Using recent AI-based approaches for protein structure prediction (AlphaFold3, RoseTTAFold All-Atom, Chai-1), we generated 14,178 models of PTM-modified human proteins with docked ligands. Our results demonstrate that these methods can predict PTM effects on small molecule binding, but precise evaluation of their accuracy requires a much larger benchmarking set. We also found that phosphorylation of NADPH-Cytochrome P450 Reductase, observed in cervical and lung cancer, causes significant structural disruption in the binding pocket, potentially impairing protein function. All data and generated models are available from DrugDomain database v1.1 (http://prodata.swmed.edu/DrugDomain/) and GitHub (https://github.com/kirmedvedev/DrugDomain). This resource is the first to our knowledge in offering structural context for small molecule binding-associated PTMs on a large scale.

Keywords:  Domain; drug discovery; drugs; post-translational modification; protein structure; protein-drug interaction; small molecule

DOI:  https://doi.org/10.1101/2025.01.14.633078
Cell Death Discov. 2025 Mar 31. 11(1): 125

Functions and mechanisms of non-histone post-translational modifications in cancer progression.

Zongyang Li, Tao Zhu, Yushu Wu, Yongbo Yu, Yunjiang Zang, Lebo Yu, Zhilei Zhang.

Protein post-translational modifications (PTMs) refer to covalent and enzymatic alterations to folded or nascent proteins during or after protein biosynthesis to alter the properties and functions of proteins. PTMs are modified in a variety of types and affect almost all aspects of cell biology. PTMs have been reported to be involved in cancer progression by influencing multiple signaling pathways. The mechanism of action of histone PTMs in cancer has been extensively studied. Notably, evidence is mounting that PTMs of non-histone proteins also play a vital role in cancer progression. In this review, we provide a systematic description of main non-histone PTMs associated with cancer progression, including acetylation, lactylation, methylation, ubiquitination, phosphorylation, and SUMOylation, based on recent studies.

DOI: https://doi.org/10.1038/s41420-025-02410-2
bioRxiv. 2025 Mar 19. pii: 2025.03.19.644084. [Epub ahead of print]

14-3-3ε UFMylation promotes RIG-I-mediated signaling.

Isaura Vanessa Gutierrez, Moonhee Park, Lauren Sar, Ryan Rodriguez, Daltry L Snider, Gabriella Torres, K Matthew Scaglione, Stacy M Horner.

Post-translational modifications are critical for regulating the RIG-I signaling pathway. Previously, we identified a role for the post-translation modification UFM1 (UFMylation) in promoting RIG-I signaling by stimulating the interaction between RIG-I and its membrane-targeting protein 14-3-3ε. Here, we identify UFMylation of 14-3-3ε as a novel regulatory mechanism promoting RIG-I signaling. We demonstrate that UFM1 conjugation to lysine residue K50 or K215 results in mono-UFMylation on 14-3-3ε and enhances its ability to promote RIG-I signaling. Importantly, we show that mutation of these residues (K50R/K215R) abolishes UFMylation and impairs induction of type I and III interferons without disrupting the interaction between 14-3-3ε and RIG-I. This suggests that UFMylation of 14-3-3ε likely stabilizes signaling events downstream of RIG-I activation to promote induction of interferon. Collectively, our work suggests that UFMylation-driven activation of 14-3-3ε facilitates innate immune signaling and highlights the broader role of UFMylation for antiviral defense and immune regulation.
Importance: Post-translational modifications provide regulatory control of antiviral innate immune responses. Our study reveals that UFMylation of 14-3-3ε is a control point for RIG-I-mediated antiviral signaling. We demonstrate that conjugation of UFM1 to specific lysine residues on 14-3-3ε enhances downstream signaling events that facilitate interferon induction, but surprisingly it does not affect 14-3-3ε binding to RIG-I. By identifying the precise sites of UFMylation on 14-3-3ε and their functional consequences, we provide insights into the regulatory layers governing antiviral innate immunity. These findings complement emerging evidence that UFMylation serves as a versatile modulator across diverse immune pathways. Furthermore, our work highlights how protein chaperones like 14-3-3ε can be dynamically modified to orchestrate complex signaling cascades, suggesting potential therapeutic approaches for targeting dysregulated innate immunity.

DOI: https://doi.org/10.1101/2025.03.19.644084
QRB Discov. 2025 ;6 e6

Filling in missing puzzle pieces in protein structural biology with cross-linking mass spectrometry.

Zheng Ser.

  High resolution structures of protein complexes provide a wealth of information on protein structure and function. Databases of these protein structures are also used for artificial-intelligence (AI)-based methods of structural modelling. Despite the wealth of protein structures that have been determined by structural biologists, there are still gaps, or missing pieces in the puzzle of protein structural biology. Highly flexible regions may be missing from protein structures and conformational changes of different protein complex states may not be captured by current databases. In this perspective, I sketch out several ways that cross-linking mass spectrometry can contribute to filling in some of these missing pieces: Identification of cross-linked interactions in highly flexible protein regions not captured by other structural techniques; capturing conformational changes of protein complexes in different functional states; serving as distance constraints in integrative structural modelling and providing structural information of in cellulo proteins. The myriad ways in which cross-linking mass spectrometry contributes to filling in missing pieces in structural biology makes it a powerful technique in structural biology.

Keywords:  cross-linking mass spectrometry; integrative structural modelling; protein complex; protein-protein interactions; structural biology

DOI:  https://doi.org/10.1017/qrd.2024.13
Ecol Evol. 2025 Apr;15(4): e71220

Correction to "Rewiring the Vehicle: Trypanosoma cruzi Parasites Alter the Antennae of Their Triatomine Hosts".

[This corrects the article DOI: 10.1002/ece3.71164.].

DOI: https://doi.org/10.1002/ece3.71220
Front Microbiol. 2025 ;16 1566579

Metagenomic detection of protozoan parasites on leafy greens aided by a rapid and efficient DNA extraction protocol.

Sohail Naushad, Ruimin Gao, Marc-Olivier Duceppe, Andree Ann Dupras, Sarah J Reiling, Harriet Merks, Brent Dixon, Dele Ogunremi.

   Introduction: Infections with protozoan parasites associated with the consumption of fresh produce is an on-going issue in developed countries but mitigating the risk is hampered by the lack of adequate methods for their detection and identification.
Materials and methods: We developed a metagenomic next-generation sequencing (mNGS) assay using a MinION sequencer for the identification of parasites in intentionally contaminated lettuce to achieve a more accurate and rapid method than the traditional molecular and microscopy methods commonly used for regulatory purposes. Lettuce (25 g) was spiked with varying numbers of Cryptosporidium parvum oocysts, and microbes washed from the surface of the lettuce were lysed using the OmniLyse device. DNA was then extracted by acetate precipitation, followed by whole genome amplification. The amplified DNA was sequenced by nanopore technology and validated with the Ion Gene Studio S5, and the generated fastq files raw reads were uploaded to the CosmosID webserver for the bioinformatic identification of microbes in the metagenome. To demonstrate the ability of the procedure to distinguish other common food and waterborne protozoan parasites, lettuce was also spiked with C. hominis, C. muris, Giardia duodenalis and Toxoplasma gondii individually or together.
Results: The efficient lysis of oocysts and cysts was a prerequisite for the sensitive detection of parasite DNA and was rapidly achieved within 3 min. Amplification of extracted DNA led to the generation of 0.16-8.25 μg of DNA (median = 4.10 μg), sufficient to perform mNGS. Nanopore sequencing followed by bioinformatic analysis led to the consistent identification of as few as 100 oocysts of C. parvum in 25 g of fresh lettuce. Similar results were obtained using the Ion S5 sequencing platform. The assay proved useful for the simultaneous detection of C. parvum, C. hominis, C. muris, G. duodenalis and T. gondii.
Discussion: Our metagenomic procedure led to the identification of C. parvum present on lettuce at low numbers and successfully identified and differentiated other protozoa either of the same genus or of different genera. This novel mNGS assay has the potential for application as a single universal test for the detection of foodborne parasites, and the subtyping of parasites for foodborne outbreak investigations and surveillance studies.

Keywords:  Cryptosporidium; Giardia; MinION; Toxoplasma; diagnostics; metagenomics

DOI:  https://doi.org/10.3389/fmicb.2025.1566579
Mol Biol Cell. 2025 Apr 02. mbcE24040162

A dual reporter system for intracellular and extracellular amino acid sensing in budding yeast.

Jurgita Paukštytė, Emma Cervera Tena, Juha Saarikangas.

Amino acid homeostasis is essential for cellular functions such as growth, metabolism, and signaling. In budding yeast Saccharomyces cerevisiae, the General Amino Acid Control (GAAC) and Target of Rapamycin Complex 1 (TORC1) pathways are utilized for intracellular amino acid sensing, while the Ssy1-Ptr3-Ssy5 (SPS) pathway is used for extracellular sensing. These pathways maintain homeostasis by responding to variations in amino acid levels to regulate amino acid biosynthesis and uptake. However, their interactions under various conditions and behavior at single-cell resolution remain insufficiently understood. We developed fluorescent transcriptional reporters to monitor amino acid biosynthesis and uptake pathways in single cells, revealing pathway engagement in response to different amino acid levels and types. Inhibition experiments demonstrated that the SPS pathway influences TORC1 and GAAC activities differently. Additionally, pathway engagement varied between liquid culture and colony environments. In colonies, some cells specialized in either amino acid synthesis or uptake. Disruption of the SPS pathway hindered this specialization and increased cell death rates in aging colonies, indicating a role for metabolic differentiation in maintaining colony viability. Collectively, this study introduces a new tool for exploring cellular amino acid homeostasis and highlights the importance of cellular differentiation in amino acid control for colony survival.

DOI: https://doi.org/10.1091/mbc.E24-04-0162
Mol Plant. 2025 Mar 31. pii: S1674-2052(25)00109-1. [Epub ahead of print]

Two E-clade Protein Phosphatase 2Cs enhance ABA signaling by dephosphorylating ABI1 in Arabidopsis.

Ya Zhang, Liyuan Han, Junjie Liu, Miao Chang, Chuanling Li, Jian-Xiu Shang, Zhiping Deng, Wenqiang Tang, Yu Sun.

  ABA INSENSITIVE 1 (ABI1) and ABI2 are co-receptors of the phytohormone abscisic acid (ABA). Studies have demonstrated that phosphorylation of multiple amino acids on ABI1/2 augments their ability to inhibit ABA signaling in planta. However, it is currently unknown whether there exists a mechanism to regulate the dephosphorylation of ABI1/2 that enhances the plant's sensitivity to ABA. In this study, we identified two protein phosphatases, designated ABI1 Dephosphorylating E clade PP2C 1 (ADEP1) and ADEP2, that interact with ABI1/2. Mutants lacking ADEP1, ADEP2, or both (adep1/2) exhibited reduced sensitivity to ABA-inhibited seed germination, root growth and ABA-induced stomatal closure. Additionally, ABA-induced accumulation of ABI5 protein and the expression of downstream target genes were reduced in the adep1/2 mutant compared to the wild-type. These findings suggest that ADEP1/2 function as positive regulators of the ABA signaling pathway. Mass spectrometry analysis and two-dimensional electrophoresis identified Ser117 as a major ABA-induced phosphorylation site on ABI1 protein. ADEP1/2 can dephosphorylate Ser117, leading to the destabilization of ABI1 protein and increased sensitivity to ABA in plants. Moreover, ABA treatment decreases the abundance of ADEP1/2 proteins. Overall, our study discovers two novel regulatory proteins that modulate ABA signaling and provides new insights into the regulatory network that fine-tune plant ABA responses.

Keywords:  ABA response; ABI1; Abscisic acid signaling; E clade protein phosphatase 2C; dephosphorylation

DOI:  https://doi.org/10.1016/j.molp.2025.03.019
Sheng Wu Gong Cheng Xue Bao. 2025 Mar 25. 41(3): 1098-1111

[Research progress in energy metabolism design of cell factories].

Yiqun Yang, Qingqing Liu, Shuo Tian, Tao Yu.

  Energy metabolism regulation plays a pivotal role in metabolic engineering. It mainly achieves the balance of material and energy metabolism or maximizes the utilization of materials and energy by regulating the supply intensity and mode of ATP and reducing electron carriers in cells. On the one hand, the production efficiency can be increased by changing the distribution of material metabolic flow. On the other hand, the thermodynamic parameters of enzyme-catalyzed reactions can be altered to affect the reaction balance, and thus the production costs are reduced. Therefore, energy metabolism regulation is expected to become a favorable tool for the modification of microbial cell factories, thereby increasing the production of target metabolites and reducing production costs. This article introduces the commonly used energy metabolism regulation methods and their effects on cell factories, aiming to provide a reference for the efficient construction of microbial cell factories.

Keywords:  cell factory; energy metabolism design; oxidative phosphorylation; substrate level phosphorylation

DOI:  https://doi.org/10.13345/j.cjb.240565
Arthritis Rheumatol. 2025 Apr 02.

Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation.

Huanhuan Liu, Anupama Binoy, Siqi Ren, Thomas C Martino, Anna E Miller, Craig R G Willis, Shivakumar R Veerabhadraiah, Joanna Bons, Jacob P Rose, Birgit Schilling, Michael J Jurynec, Shouan Zhu.

OBJECTIVES: Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development.
METHODS: Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5-/- and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB).
RESULTS: We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK's predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe-F) to leucine (Leu-L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes.
CONCLUSIONS: We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.

DOI: https://doi.org/10.1002/art.43164
Adv Sci (Weinh). 2025 Apr 01. e2412921

Histone Deacetylase 6 (HDAC6) in Ciliopathies: Emerging Insights and Therapeutic Implications.

Zhiyi Wang, Xiaofan Zhu, Zhenzhou Huang, Kaidi Ren, Jie Ran, Yang Yang.

  HDAC6 is integral to the regulation of primary cilia, which are specialized structures that serve as crucial signaling hubs for cellular communication and environmental response. These ciliary functions are essential for maintaining cellular homeostasis and orchestrating developmental processes. Dysregulation of HDAC6 activity is implicated in ciliopathies, a group of disorders characterized by defective ciliary structure or function, resulting in widespread organ involvement and significant morbidity. This review provides a comprehensive examination of the molecular dynamics of HDAC6 in the context of ciliogenesis and ciliopathies, emphasizing its dual role in the deacetylation of microtubules and regulation of the ciliary axoneme. Furthermore, HDAC6 interacts with key signaling molecules, modulating processes ranging from cell cycle regulation to inflammatory responses, which highlights its central role in cellular physiology and pathology. The therapeutic potential of HDAC6 inhibitors has been explored, with promising results in various disease models, including retinal and renal ciliopathies, highlighting their ability to restore normal ciliary function. This analysis not only underscores the critical importance of HDAC6 in maintaining ciliary integrity but also illustrates how targeting the HDAC6-cilia axis could provide a groundbreaking approach to treating these complex disorders. In doing so, this review sets the stage for future investigations into HDAC6-targeted therapies, potentially transforming the clinical management of ciliopathies and significantly improving patient outcomes.

Keywords:  HDAC6 inhibitors; cilia; ciliopathy; histone deacetylase 6; therapeutic implications

DOI:  https://doi.org/10.1002/advs.202412921