bims-toxgon 2024-11-03 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2024–11–03
twenty-six papers selected by
Lakesh Kumar, BITS Pilani

Characterization of two phosphatase 2C domain-containing proteins PPM2A and PPM2B in Toxoplasma gondii.
Kinase function of TgTKL1 is essential for its role in Toxoplasma propagation and pathogenesis.
In silico analysis and structural vaccinology prediction of Toxoplasma gondii ROP41 gene via immunoinformatics methods as a vaccine candidate.
Characterization of atypical BAR domain-containing proteins coded by Toxoplasma gondii.
Toxoplasma gondii ROP5 Enhances Type I IFN Responses by Promoting Ubiquitination of STING.
Histone Deacetylases in Metabolism: The Known and the Unexplored.
Evaluation of protective efficacy of recombinant Toxoplasma gondii DDX39 protein vaccine against acute and chronic T. gondii infection in mice.
Targeting sirtuins for cancer therapy: epigenetics modifications and beyond.
Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity.
Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites.
Trend in serological and molecular diagnostic methods for Toxoplasma gondii infection.
The role of host autophagy in intracellular protozoan parasites diseases.
ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.
Serum Biomarker Concentrations upon Admission in Acute Traumatic Brain Injury: Associations with TBI Severity, Toxoplasma gondii Infection, and Outcome in a Referral Hospital Setting in Cameroon.
Phosphorylation in the Plasmodium falciparum Proteome: A Meta-Analysis of Publicly Available Data Sets.
Ca+2 and Nε-lysine acetylation regulate the CALR-ATG9A interaction in the lumen of the endoplasmic reticulum.
Unraveling the role of cAMP signaling in Giardia: insights into PKA-mediated regulation of encystation and subcellular interactions.
Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury.
Coinfection of Toxoplasma gondii and Other Microorganisms: A Systematic Review and Meta-Analysis.
Precision proteomics with TurboID: mapping the suborganelle landscape.
Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off-target effects.
Establishment of the auxin inducible degron system for Babesia duncani: a conditional knockdown tool to study precise protein regulation in Babesia spp.
An ATP detection system based on the enzyme reaction with biotin protein ligase.
Cracking Lysine Crotonylation (Kcr): Enlightening a Promising Post-Translational Modification.
The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.
Acetylation of Histone H3 in Cancer Progression and Prognosis.

Mol Biochem Parasitol. 2024 Oct 24. pii: S0166-6851(24)00047-1. [Epub ahead of print] 111654

Characterization of two phosphatase 2C domain-containing proteins PPM2A and PPM2B in Toxoplasma gondii.

Ao Zeng, Yongle Song, Xiaoting Wan, Bang Shen, Rui Fang, Junlong Zhao, Yanqin Zhou.

  Protein phosphatases Mg2+/Mn2+ dependent (PPMs), serine/threonine phosphatases, are widely distributed in apicomplexan parasites, and Toxoplasma gondii possesses the largest number of PPMs in the apicomplexan parasites. Though the function of some PPMs has been characterized in T. gondii, much less is known about two phosphatase 2C domain-containing proteins, PPM2A and PPM2B. PPM2A was identified as one of Toxoplasma Calmodulin's interacting proteins through proximity-based protein interaction BioID technology in the previous study, and PPM2B was the homolog of PPM2A in T. gondii. In this study, PPM2A was distributed in the whole tachyzoite of T. gondii, and PPM2B was mainly distributed in the cytoplasm by inserting a 10HA tag in the C-terminus of the two genes in the RH∆ku80 strain. PPM2A knockout (Δppm2a), PPM2B knockout (Δppm2b), and double knockout (ΔΔ) in RHΔhxgprt type I strain under CRISPR-Cas9 system did not result in intracellular replication defect. Besides, mouse experiments demonstrated that PPM2A, PPM2B, and double knockout did not reduce the pathogenicity of T. gondii compared with the RH∆hxgprt strain. However, the plaque size of these single knockout and double knockout strains were smaller than that in the control RH∆hxgprt strain. Our results provide new insight into the function of PPMs in the pathogenesis of T. gondii.

Keywords:  PPM2A; PPM2B; Phenotype; Subcellular localization; Toxoplasma gondii; Virulence

DOI:  https://doi.org/10.1016/j.molbiopara.2024.111654
mSphere. 2024 Oct 30. e0077924

Kinase function of TgTKL1 is essential for its role in Toxoplasma propagation and pathogenesis.

Dima Hajj Ali, Ramu Anandakrishnan, Vern B Carruthers, Rajshekhar Y Gaji.

  The Tyrosine Kinase-Like (TKL) family of proteins are a set of poorly studied kinases that have garnered attention in recent years for their role in Toxoplasma biology. The Toxoplasma genome contains eight TKL kinases, of which six have been predicted to be important for parasite propagation. We have previously shown that TgTKL1 is a nuclear kinase that is critical for the parasite lytic cycle and is essential for acute virulence in the animal model. However, the contribution of the kinase domain to the functioning of TgTKL1 was not known. Hence to determine the significance of its catalytic function, we first validated that TgTKL1 is a true kinase using purified recombinant protein. Furthermore, we successfully generated a TgTKL1 kinase mutant strain of Toxoplasma via CRISPR-Cas9 gene editing. Our studies revealed that the kinase mutant of TgTKL1 displays defects in parasite growth and host-cell invasion. Additionally, loss of kinase function alters the transcriptomic profile of the parasite, including downregulation of the invasion-related gene, TgSUB1. Importantly, this dysregulation of TgSUB1 expression leads to defects in post-exocytosis processing of micronemal proteins, an event critical for normal host-cell invasion. Furthermore, the TgTKL1 kinase mutant is completely avirulent in the mouse model of acute toxoplasmosis. Since the loss of kinase function leads to phenotypic manifestations seen previously with TgTKL1 knockout parasites, we conclude that kinase activity is important for TgTKL1 function in Toxoplasma propagation and virulence.
IMPORTANCE: Toxoplasma gondii is a protozoan parasite that can cause life-threatening disease in humans. Hence, identifying key factors required for parasite growth and pathogenesis is important to develop novel therapeutics. We have previously shown that a member of the TKL protein kinase family, TgTKL1, is a plant-like kinase that is required for effective Toxoplasma growth in vitro and essential for virulence in vivo. Herein, we show that the TgTKL1 is, indeed, a bona fide kinase, and loss of its kinase function in the Toxoplasma leads to similar defects seen in parasites with complete loss of TgTKL1. More specifically, the TgTKL1 kinase mutant exhibits defects in parasite growth, host-cell invasion, gene expression profile, and virulence in the animal model. Together, these findings suggest that TgTKL1 is a true kinase, and loss of its kinase activity leads to disruption of TgTKL1 function in Toxoplasma.

Keywords:  Toxoplasma gondii; apicomplexan parasites; kinases

DOI:  https://doi.org/10.1128/msphere.00779-24
Curr Res Transl Med. 2024 Oct 16. pii: S2452-3186(24)00037-0. [Epub ahead of print]73(1): 103475

In silico analysis and structural vaccinology prediction of Toxoplasma gondii ROP41 gene via immunoinformatics methods as a vaccine candidate.

Masoumeh Asadi, Ali Dalir Ghaffari, Fatemeh Mohammadhasani.

   INTRODUCTION: Toxoplasma gondii (T. gondii) infects all warm-blooded animals, including humans. Currently, no effective treatments exist to prevent the generation of chronic tissue cysts in infected hosts. Therefore, developing a vaccine to protect to deal with toxoplasmosis is a promising strategy, as a single immunization could provide lifelong protective immunity. Rhoptry proteins (ROPs) play a vital role for the parasite's survival within host cells and perform critical functions during different phases of parasite invasion. Little is known about ROP41 gene. Nevertheless, Understanding the characteristics of ROP41 will enhance diagnostic and vaccine research.
MATERIALS AND METHODS: The current article provides a comprehensive analysis of the essential components of the ROP41 protein, including its transmembrane domain, physico-chemical properties, subcellular location, tertiary and secondary structures, and potential T- and B-cell epitopes. These features were determined by many bioinformatics approaches to identify possible epitopes for developing a highly effective vaccine.
RESULTS: ROP41 protein showed 36 possible post-translational modification regions. The ROP41 protein secondary structure contains 17.35 % extended strand, 33.47 % alpha-helix, and 49.18 % random coil. Also, ROP41 showed many possible B- and T-cell epitopes. According to the Ramachandran plot, 90.78 % of amino acid residues had been placed in favored, 3.28 % in outlier, and 5.94 % in allowed areas. Also, the allergenicity and antigenicity evaluation indicated that ROP41 is non-allergenic and immunogenic.
CONCLUSION: The current study offered critical basic and conceptual information on ROP41 to increase a successful vaccine in opposition to continual and acute toxoplasmosis for in addition in vivo assessments. Further research is necessary for the development of vaccines utilizing ROP41 alone or combined with various antigens.

Keywords:  Bioinformatics; Computational biology; ROP41; Toxoplasma gondii; Vaccines

DOI:  https://doi.org/10.1016/j.retram.2024.103475
J Biol Chem. 2024 Oct 24. pii: S0021-9258(24)02425-6. [Epub ahead of print] 107923

Characterization of atypical BAR domain-containing proteins coded by Toxoplasma gondii.

Noha Al-Qatabi, Maud Magdeleine, Sophie Pagnotta, Amélie Leforestier, Jéril Degrouard, Ana Andreea Arteni, Sandra Lacas-Gervais, Romain Gautier, Guillaume Drin.

  Toxoplasma gondii, the causative agent of toxoplasmosis, infects cells and replicates inside via the secretion of factors stored in specialized organelles (rhoptries, micronemes, dense granules) and the capture of host materials. The genesis of the secretory organelles and the processes of secretion and endocytosis depend on vesicular trafficking events whose molecular bases remain poorly known. Notably, there is no characterization of the BAR (Bin/Amphiphysin/Rvs) domain-containing proteins expressed by T. gondii and other apicomplexans, although such proteins are known to play critical roles in vesicular trafficking in other eukaryotes. Here, by combining structural analyses with in vitro assays and cellular observations, we have characterized TgREMIND (REgulators of Membrane Interacting Domains), involved in the genesis of rhoptries and dense granules, and TgBAR2 found at the parasite cortex. We establish that TgREMIND comprises an F-BAR domain that can bind curved neutral membranes with no strict phosphoinositide requirement and exert a membrane remodeling activity. Next, we establish that TgREMIND contains a new structural domain called REMIND, which negatively regulates the membrane-binding capacities of the F-BAR domain. In parallel, we report that TgBAR2 contains a BAR domain with an extremely basic membrane-binding interface able to deform anionic membranes into very narrow tubules. Our data show that T. gondii codes for two atypical BAR domain-containing proteins with very contrasting membrane-binding properties, allowing them to function in two distinct regions of the parasite trafficking system.

Keywords:  Toxoplasma gondii; liposome; membrane trafficking; microscopy; phosphoinositide; protein‐lipid interaction; recombinant protein; spectroscopy; structural model

DOI:  https://doi.org/10.1016/j.jbc.2024.107923
Int J Mol Sci. 2024 Oct 19. pii: 11262. [Epub ahead of print]25(20):

Toxoplasma gondii ROP5 Enhances Type I IFN Responses by Promoting Ubiquitination of STING.

Qi-Wang Jin, Ting Yu, Ming Pan, Yi-Min Fan, Ceng-Ceng Ge, Xiao-Bing He, Jing-Zhi Gong, Jian-Ping Tao, Bao-Quan Fu, Zhi-Zhong Jing, Si-Yang Huang.

  Toxoplasma gondii is a widely spread opportunistic pathogen that can infect nearly all warm-blooded vertebrates and cause serious toxoplasmosis in immunosuppressed animals and patients. However, the relationship between the host's innate immune system and effector proteins is poorly understood, particularly with regard to how effectors antagonize cGAS-STING signaling during T. gondii infection. In this study, the ROP5 from the PRU strain of T. gondii was found to promote cGAS-STING-mediated immune responses. Mechanistically, ROP5 interacted with STING through predicted domain 2 and modulated cGAS-STING signaling in a predicted domain 3-dependent manner. Additionally, ROP5 strengthened cGAS-STING signaling by enhancing the K63-linked ubiquitination of STING. Consistently, ROP5 deficient PRU (PRUΔROP5) induced fewer type I IFN-related immune responses and replicated faster than the parental strain in RAW264.7 cells. Taken together, this study provides new insights into the mechanism by which ROP5 regulates T. gondii infection and provides new clues for strategies to prevent and control toxoplasmosis.

Keywords:  ROP5; Toxoplasma gondii; cGAS-STING pathway; ubiquitination

DOI:  https://doi.org/10.3390/ijms252011262
Physiology (Bethesda). 2024 Oct 29.

Histone Deacetylases in Metabolism: The Known and the Unexplored.

Somaya Y Ibrahim, Jayden Carter, Rushita A Bagchi.

  Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from key lysine residues on histone and non-histone proteins and thereby regulate gene transcription. They have been implicated in several biological processes in both healthy and pathologic settings. This review discusses the role of HDACs in multiple metabolically active tissues and highlights their contribution to the pathogenesis of tissue-specific maladaptation and diseases. We also summarize the current knowledge gaps and potential ways to address them in future studies.

Keywords:  Chromatin; Gene expression; HDAC inhibitors; Histone deacetylase; Metabolism

DOI:  https://doi.org/10.1152/physiol.00044.2024
Acta Trop. 2024 Oct 24. pii: S0001-706X(24)00323-1. [Epub ahead of print]260 107442

Evaluation of protective efficacy of recombinant Toxoplasma gondii DDX39 protein vaccine against acute and chronic T. gondii infection in mice.

Jinghui Wang, Yuanfeng Wang, Haina Zhang, Hangbin Ma, Qiangqiang Wang, Longkang Wang, Youke Fan, Xiaowei Tian, Xuefang Mei, Zhenchao Zhang, Shuai Wang, Zhenke Yang.

  Toxoplasma gondii, a pervasive parasite responsible for toxoplasmosis, poses significant health risks to humans and animals. In this study, we investigated the immunogenicity and protective efficacy of the recombinant T. gondii DDX39 protein formulated with ISA201 adjuvant (rTgDDX39) as a candidate vaccine against toxoplasmosis. The full-length of TgDDX39 gene was successfully amplified, cloned into the pET-30a vector, and expressed in BL21 (DE3) competent cells, which was purified and identified as a 57.1 kDa protein via sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Western blot analysis confirmed that rTgDDX39 was specifically recognized by serum from T. gondii-infected mice. Furthermore, immunization of rats with rTgDDX39 generated antiserum that could specifically recognize the native TgDDX39 protein in T. gondii tachyzoite lysates. Immunofluorescence assay revealed that TgDDX39 was primarily located in the nucleus and perinuclear region of tachyzoites. Our vaccination strategy significantly increased T cell proliferation, with CD4+T cells rising by 21.9% and CD8+T cells by 57.8% by the sixth week compared to the adjuvant control group. Additionally, high titers of anti-rTgDDX39 IgG antibodies were detected in vaccinated mice, with a notable induction of IgG1 and IgG2a isotypes, and IgG1/IgG2a > 1 suggests a Th2-biased immune response. Furthermore, in vitro and in vivo assays demonstrated that polyclonal antibodies raised against rTgDDX39 could inhibit the proliferation of T. gondii RH tachyzoites, highlighting the potential of these antibodies to neutralize this parasite effectively. This study provides compelling evidence of the immunogenicity and protective efficacy of rTgDDX39, supporting its potential as a potential candidate vaccine against toxoplasmosis. The protective efficacy of the vaccine was evaluated in mice challenged with acute (RH) and chronic (PRU) strains of T. gondii, showing a survival time extended to 17 days in the acute model, compared to 13.5 and 14 days in the control groups, and a significant 34% reduction in cyst burden in the chronic model. Additionally, the survival rate in the PRU-infected mice increased from 15 to 20% in the control groups to 45% in the vaccinated group. In vitro and in vivo assays demonstrated that polyclonal antibodies raised against rTgDDX39 could inhibit the proliferation of T. gondii RH tachyzoites, highlighting the potential of these antibodies to neutralize the parasite effectively. This study provides compelling evidence of the immunogenicity and protective efficacy of rTgDDX39, supporting its potential as a candidate vaccine against toxoplasmosis.

Keywords:  DDX39; Dead-box; Protective efficacy; Recombinant subunit vaccine; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.actatropica.2024.107442
Theranostics. 2024 ;14(17): 6726-6767

Targeting sirtuins for cancer therapy: epigenetics modifications and beyond.

Hui Shen, Xinyi Qi, Yue Hu, Yi Wang, Jin Zhang, Zhongyu Liu, Zheng Qin.

  Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide+(NAD+)-dependent histone deacetylases, which are important epigenetic enzymes consisting of seven family members (SIRT1-7). Of note, SIRT1 and SIRT2 are distributed in the nucleus and cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in the mitochondria. SIRT6 and SIRT7 are distributed in the nucleus. SIRTs catalyze the deacetylation of various substrate proteins, thereby modulating numerous biological processes, including transcription, DNA repair and genome stability, metabolism, and signal transduction. Notably, accumulating evidence has recently underscored the multi-faceted roles of SIRTs in both the suppression and progression of various types of human cancers. Crucially, SIRTs have been emerging as promising therapeutic targets for cancer therapy. Thus, in this review, we not only present an overview of the molecular structure and function of SIRTs, but elucidate their intricate associations with oncogenesis. Additionally, we discuss the current landscape of small-molecule activators and inhibitors targeting SIRTs in the contexts of cancer and further elaborate their combination therapies, especially highlighting their prospective utility for future cancer drug development.

Keywords:  Cancer therapy; Epigenetics modification; Sirtuin (SIRT); Small-molecule activator; Small-molecule inhibitor

DOI:  https://doi.org/10.7150/thno.100667
Pharmaceuticals (Basel). 2024 Sep 29. pii: 1298. [Epub ahead of print]17(10):

Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity.

Thomas Shenk, John L Kulp Iii, Lillian W Chiang.

  Direct-acting anti-infective drugs target pathogen-coded gene products and are a highly successful therapeutic paradigm. However, they generally target a single pathogen or family of pathogens, and the targeted organisms can readily evolve resistance. Host-targeted agents can overcome these limitations. One family of host-targeted, anti-infective agents modulate human sirtuin 2 (SIRT2) enzyme activity. SIRT2 is one of seven human sirtuins, a family of NAD+-dependent protein deacylases. It is the only sirtuin that is found predominantly in the cytoplasm. Multiple, structurally distinct SIRT2-targeted, small molecules have been shown to inhibit the replication of both RNA and DNA viruses, as well as intracellular bacterial pathogens, in cell culture and in animal models of disease. Biochemical and X-ray structural studies indicate that most, and probably all, of these compounds act as allosteric modulators. These compounds appear to impact the replication cycles of intracellular pathogens at multiple levels to antagonize their replication and spread. Here, we review SIRT2 modulators reported to exhibit anti-infective activity, exploring their pharmacological action as anti-infectives and identifying questions in need of additional study as this family of anti-infective agents advances to the clinic.

Keywords:  SIRT1; SIRT2; allostery; anti-infective; antiviral; epigenetics; host cell metabolism; host-targeted agents; sirtuin

DOI:  https://doi.org/10.3390/ph17101298
Proc Natl Acad Sci U S A. 2024 Nov 05. 121(45): e2411631121

Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites.

Kade M Loveridge, Paul A Sigala.

  Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. falciparum requires nutritional iron to support essential metabolic pathways, but the critical mechanisms of iron acquisition and trafficking during RBC infection have remained obscure. Parasites internalize and liberate massive amounts of heme during large-scale digestion of RBC hemoglobin within an acidic food vacuole (FV) but lack a heme oxygenase to release porphyrin-bound iron. Although most FV heme is sequestered into inert hemozoin crystals, prior studies indicate that trace heme escapes biomineralization and is susceptible to nonenzymatic degradation within the oxidizing FV environment to release labile iron. Parasites retain a homolog of divalent metal transporter 1 (DMT1), a known mammalian iron transporter, but its role in P. falciparum iron acquisition has not been tested. Our phylogenetic studies indicate that P. falciparum DMT1 (PfDMT1) retains conserved molecular features critical for metal transport. We localized this protein to the FV membrane and defined its orientation in an export-competent topology. Conditional knockdown of PfDMT1 expression is lethal to parasites, which display broad cellular defects in iron-dependent functions, including impaired apicoplast biogenesis and mitochondrial polarization. Parasites are selectively rescued from partial PfDMT1 knockdown by supplementation with exogenous iron, but not other metals. These results support a cellular paradigm whereby PfDMT1 is the molecular gatekeeper to essential iron acquisition by blood-stage malaria parasites and suggest that therapeutic targeting of PfDMT1 may be a potent antimalarial strategy.

Keywords:  Plasmodium; digestive vacuole; iron; malaria; metal transporter

DOI:  https://doi.org/10.1073/pnas.2411631121
Eur J Med Res. 2024 Oct 28. 29(1): 520

Trend in serological and molecular diagnostic methods for Toxoplasma gondii infection.

Min-Ju Kim, Soeun J Park, Hyunwoo Park.

   BACKGROUND: Toxoplasma gondii, an intracellular parasite, is a significant cause of zoonotic disease, with an estimated one-third of the world's human population believed to be infected. T. gondii is transmitted to humans through the consumption of contaminated water, soil, vegetables, fruits, shellfish or undercooked meat, and can also be passed from human to human through vertical transmission, transplants and blood transfusion. While T. gondii infection typically manifests mild symptoms such as colds among immunocompetent individuals, it can prove lethal for those with weakened immune systems.
METHODS: To summarize the diagnostic methods for Toxoplasma gondii infection, we performed a literature search on PubMed from 1948 to 2023 using the keywords "T. gondii serological diagnosis" or "T. gondii molecular diagnosis".
RESULTS: Rapid and accurate diagnosis of T. gondii infection is imperative. Although a diagnostic kit is currently commercially available, there are a number of disadvantages to the validation principles applied to each diagnostic kit. Consequently, multiple diagnostic methods are concurrently employed to offset these limitations. Serological methods for diagnosing T. gondii infection include the Dye Test (DT), Agglutination Test (AT), Modified Agglutination Test (MAT), Latex Agglutination Test (LAT), Enzyme-Linked Immunosorbent Assay (ELISA), and Western Blot. Meanwhile, molecular methods such as polymerase chain reaction (PCR), nested PCR, real-time PCR, loop-mediated isothermal amplification (LAMP), multiplex PCR, and PCR-restriction fragment length polymorphism (PCR-RFLP) are also utilized. Each of these methods possess its own set of advantages and disadvantages.
CONCLUSIONS: By summarizing the advantages and disadvantages of different diagnostic techniques, it is hoped that the epidemiology, prevention, and control of toxoplasmosis will be improved in the future through the use of appropriate technologies.

Keywords:   Toxoplasma gondii ; Diagnosis; Sensitivity; Specificity; Toxoplasmosis

DOI:  https://doi.org/10.1186/s40001-024-02055-4
Arch Biochem Biophys. 2024 Oct 23. pii: S0003-9861(24)00308-4. [Epub ahead of print]761 110186

The role of host autophagy in intracellular protozoan parasites diseases.

Rafael Cardoso Maciel Costa Silva, Jhones Sousa Ribeiro, Thalita Santos de Moraes de Farias, Leonardo Holanda Travassos.

  Intracellular protozoan parasites are the etiologic agents of important human diseases, like malaria, Chagas disease, toxoplasmosis, and leishmaniasis. Inside host cells, these parasites manipulate the host metabolism and intracellular trafficking for their own benefits and, inevitably, induce several stress response mechanisms. In this review, we discuss autophagy as a stress response mechanism that can be both (i) explored by these intracellular parasites to acquire nutrients and (ii) to restrict parasite proliferation and survival within host cells. We also discuss the immunomodulatory role of autophagy as a strategy to reduce inflammatory-mediated damage, an essential player in the pathophysiology of these parasitic diseases. At last, we propose and discuss several known autophagy modulators as possible pharmaceuticals for adjunctive therapies.

Keywords:  Autophagy; Chagas disease; Immune response; Leishmaniasis; Malaria; Toxoplasmosis

DOI:  https://doi.org/10.1016/j.abb.2024.110186
bioRxiv. 2024 Oct 21. pii: 2024.10.18.619082. [Epub ahead of print]

ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.

Emily M Esquea, Riley G Young, Lorela Ciraku, Jessica Merzy, Nusaiba N Ahmed, Alexandra N Talarico, Mangalam Karuppiah, Wiktoria Gocal, Nicole L Simone, Alexej Dick, Mauricio J Reginato.

Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo . These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.

DOI: https://doi.org/10.1101/2024.10.18.619082
NeuroSci. 2023 Sep;4(3): 164-177

Serum Biomarker Concentrations upon Admission in Acute Traumatic Brain Injury: Associations with TBI Severity, Toxoplasma gondii Infection, and Outcome in a Referral Hospital Setting in Cameroon.

Franklin Chu Buh, Germain Sotoing Taiwe, Firas H Kobeissy, Kevin W Wang, Andrew I R Maas, Mathieu Motah, Basil Kum Meh, Eric Youm, Peter J A Hutchinson, Irene Ule Ngole Sumbele.

  Despite the available literature on traumatic brain injury (TBI) biomarkers elsewhere, data are limited or non-existent in sub-Saharan Africa (SSA). The aim of the study was to analyse associations in acute TBI between the admission serum biomarker concentrations and TBI severity, CT-scan findings, and outcome, as well as to explore the influence of concurrent Toxoplasma gondii infection. The concentrations of serum biomarkers (GFAP, NFL Tau, UCH-L1, and S100B) were measured and Toxoplasma gondii were detected in the samples obtained <24 h post injury. GOSE was used to evaluate the 6-month outcome. All of the biomarker levels increased with the severity of TBI, but this increase was significant only for NFL (p = 0.01). The GFAP values significantly increased (p = 0.026) in those with an unfavourable outcome. The Tau levels were higher in those who died (p = 0.017). GFAP and NFL were sensitive to CT-scan pathology (p values of 0.004 and 0.002, respectively). The S100B levels were higher (p < 0.001) in TBI patients seropositive to Toxoplasma gondii. In conclusion, NFL was found to be sensitive to TBI severity, while NFL and GFAP were predictive of CT intracranial abnormalities. Increased levels of GFAP and Tau were associated with poorer outcomes 6 months after TBI, and the S100B levels were significantly affected by concurrent T. gondii infection in TBI patients compared with the seronegative patients.

Keywords:  CT-scan findings; Toxoplasma gondii; outcome; serum biomarkers; traumatic brain injury

DOI:  https://doi.org/10.3390/neurosci4030015
J Proteome Res. 2024 Oct 30.

Phosphorylation in the Plasmodium falciparum Proteome: A Meta-Analysis of Publicly Available Data Sets.

Oscar J M Camacho, Kerry A Ramsbottom, Ananth Prakash, Zhi Sun, Yasset Perez Riverol, Emily Bowler-Barnett, Maria Martin, Jun Fan, Eric W Deutsch, Juan Antonio Vizcaíno, Andrew R Jones.

  Malaria is a deadly disease caused by Apicomplexan parasites of the Plasmodium genus. Several species of the Plasmodium genus are known to be infectious to humans, of which P. falciparum is the most virulent. Post-translational modifications (PTMs) of proteins coordinate cell signaling and hence regulate many biological processes in P. falciparum homeostasis and host infection, of which the most highly studied is phosphorylation. Phosphosites on proteins can be identified by tandem mass spectrometry (MS) performed on enriched samples (phosphoproteomics), followed by downstream computational analyses. We have performed a large-scale meta-analysis of 11 publicly available phosphoproteomics data sets to build a comprehensive atlas of phosphosites in the P. falciparum proteome, using robust pipelines aimed at strict control of false identifications. We identified a total of 26,609 phosphorylated sites on P. falciparum proteins, split across three categories of data reliability (gold/silver/bronze). We identified significant sequence motifs, likely indicative of different groups of kinases responsible for different groups of phosphosites. Conservation analysis identified clusters of phosphoproteins that are highly conserved and others that are evolving faster within the Plasmodium genus, and implicated in different pathways. We were also able to identify over 180,000 phosphosites within Plasmodium species beyond falciparum, based on orthologue mapping. We also explored the structural context of phosphosites, identifying a strong enrichment for phosphosites on fast-evolving (low conservation) intrinsically disordered regions (IDRs) of proteins. In other species, IDRs have been shown to have an important role in modulating protein-protein interactions, particularly in signaling, and thus warranting further study for their roles in host-pathogen interactions. All data have been made available via UniProtKB, PRIDE, and PeptideAtlas, with visualization interfaces for exploring phosphosites in the context of other data on Plasmodium proteins.

Keywords:  Plasmodium falciparum; bioinformatics; cell signaling; malaria; meta-analysis; phosphoproteomics

DOI:  https://doi.org/10.1021/acs.jproteome.4c00418
Sci Rep. 2024 10 26. 14(1): 25532

Ca+2 and Nε-lysine acetylation regulate the CALR-ATG9A interaction in the lumen of the endoplasmic reticulum.

Megan M Braun, Brendan K Sheehan, Samantha L Shapiro, Yun Ding, C Dustin Rubinstein, Brent P Lehman, Luigi Puglielli.

  The acetylation of autophagy protein 9 A (ATG9A) in the lumen of the endoplasmic reticulum (ER) by ATase1 and ATase2 regulates the induction of reticulophagy. Analysis of the ER-specific ATG9A interactome identified calreticulin (CALR), an ER luminal Ca+2-binding chaperone, as key for ATG9A activity. Specifically, if acetylated, ATG9A is sequestered by CALR and prevented from engaging FAM134B and SEC62. Under this condition, ATG9A is unable to activate the autophagy core machinery. In contrast, when non-acetylated, ATG9A is released by CALR and able to engage FAM134B and SEC62. In this study, we report that Ca+2 dynamics across the ER membrane regulate the ATG9A-CALR interaction as well as the ability of ATG9A to trigger reticulophagy. We show that the Ca+2-binding sites situated on the C-domain of CALR are essential for the ATG9A-CALR interaction. Finally, we show that K359 and K363 on ATG9A can influence the ATG9A-CALR interaction. Collectively, our results disclose a previously unidentified aspect of the complex mechanisms that regulate ATG9A activity. They also offer a possible area of intersection between Ca+2 metabolism, acetyl-CoA metabolism, and ER proteostasis.

Keywords:  ATG9A; Calcium; Calreticulin; Lysine acetylation; Proteostasis; Reticulophagy

DOI:  https://doi.org/10.1038/s41598-024-76854-4
mSphere. 2024 Oct 30. e0072324

Unraveling the role of cAMP signaling in Giardia: insights into PKA-mediated regulation of encystation and subcellular interactions.

Han-Wei Shih, Germain C M Alas, Alexander R Paredez.

  cAMP plays an important role as a second messenger in the stage transition of various protozoan parasites. This signaling pathway relies on multiple effectors, such as protein kinase A (PKA), exchange protein activated by cAMP, and cAMP-response element binding protein transcription factors, to initiate signal transduction in humans. The Giardia genome only contains two adenylate cyclases (ACs), a single phosphodiesterase (PDE) and a single known PKA effector, and the specific functions of these components are not fully understood. In our previous research, we demonstrated the important role of AC2-dependent cAMP signaling in promoting the encystation program. Using the NanoBit technology, we emphasized the significance of AC2-dependent cAMP biosynthesis in regulating the dissociation of the PKA regulatory domain (PKAr) and PKA catalytic domain (PKAc). In this study, our objectives are twofold: first, we used the newly developed Split-Halo to examine subcellular interactions of GlPKAr and GlPKAc in Giardia; and second, we investigated whether PKAc regulates encystation-specific proteins. Our findings revealed distinct subcellular locations where GlPKAr and GlPKAc interacted during the trophozoite stage, including the flagella, basal bodies, and cytoplasm. Upon exposure to encystation stimuli, the interaction shifted from the flagella to the cytosol. Knockdown of GlPKAc resulted in the downregulation of encystation-specific genes, leading to the production of fewer viable and water-resistant cysts indicating a role for PKA in the transcriptional regulation of encystation. These discoveries contribute to a deeper understanding of the cAMP signaling pathway and its important role in governing Giardia's encystation process.
IMPORTANCE: The precise timing of interactions and subcellular compartmentation play crucial roles in signal transduction. The co-immunoprecipitation assay (CO-IP) has long been utilized to validate protein-protein interactions; however, CO-IPs lack spatial and temporal resolutions. Our recent study used the NanoBit assay, which showcased the reversible protein-protein interaction between PKAr and PKAc in response to cAMP analogs and encystation stimuli. Expanding on this groundwork, this study employs the Split-Halo assay to uncover the subcellular compartments where the PKAr and PKAc protein-protein interactions take place and respond to encystation stimuli. Taken together, these molecular tools provide spatiotemporal information on the protein-protein interaction, which will be useful in the field.

Keywords:  PKA; cyclic AMP; encystationc

DOI:  https://doi.org/10.1128/msphere.00723-24
bioRxiv. 2024 Oct 25. pii: 2024.10.22.619640. [Epub ahead of print]

Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury.

Takuto Chiba, Akira Oda, Yuxun Zhang, Joanna Bons, Sivakama S Bharathi, Katherine E Pfister, Bob B Zhang, Adam C Richert, Birgit Schilling, Eric S Goetzman, Sunder Sims-Lucas.

Proximal tubular epithelial cells (PTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids are the preferred energy source for PTECs via fatty acid oxidation (FAO), FAO-mediated H 2 O 2 production in mitochondria has been shown to be a major source of oxidative stress. We have previously shown that a mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes a key step in mitochondrial FAO, directly produces H 2 O 2 in vitro . Further we have established that loss of a lysine deacylase, Sirtuin 5 ( Sirt5 -/- ), induces hypersuccinylation and inhibition of mitochondrial FAO genes to stimulate peroxisomal FAO and to protect against AKI. However, the role of LCAD has yet to be determined. Mass spectrometry data acquisition revealed that LCAD is hypersuccinylated in Sirt5 -/- kidneys after AKI. Following two distinct models of AKI, cisplatin treatment or renal ischemia/reperfusion (IRI), LCAD knockout mice ( LCAD -/- ) demonstrated renoprotection against AKI. Specifically, LCAD -/- kidneys displayed mitigated renal tubular injury, decreased oxidative stress, preserved mitochondrial function, enhanced peroxisomal FAO, and decreased ferroptotic cell death. LCAD deficiency confers protection against two distinct models of AKI. This suggests a therapeutically attractive mechanism whereby preserved mitochondrial respiration as well as enhanced peroxisomal FAO by loss of LCAD mediates renoprotection against AKI.

DOI: https://doi.org/10.1101/2024.10.22.619640
Microorganisms. 2024 Oct 21. pii: 2106. [Epub ahead of print]12(10):

Coinfection of Toxoplasma gondii and Other Microorganisms: A Systematic Review and Meta-Analysis.

María de la Luz Galván-Ramírez, Eber Eduardo Soto-Hernández, Rocío Bojórquez-Pérez.

  Toxoplasmosis is a disease caused by the intracellular protozoan Toxoplasma gondii, which has infected a third of the global population. Immunocompromised individuals and children with congenital disorders are most likely to be impacted by toxoplasmosis, and accurate diagnosis is essential. Toxoplasmosis is associated with HIV, schizophrenia, and diabetes. However, few studies have analyzed the association with other microorganisms. The purpose of this study was to determine the prevalence of coinfection of Toxoplasma gondii with other pathogens. From November 1997 to June 2024, PubMed, Science Direct, LAT index, Web of Science, Google Scholar, and Research Gate were searched. The keywords used were "Toxoplasma and microorganism coinfection", "Toxoplasma coinfection and parasites", "Toxoplasma coinfection and Protozoans or Bacteria or Helminths or Nematodes or Trematodes or Mycobacterium", "Toxoplasma gondii in coinfection with virus", and "Human Toxoplasmosis and coinfection". Next, OpenMeta Analyst Software version 12.11 was used for meta-analysis, creating forest plots, and determining heterogeneity I2. A total of 17,535 patients in 48 articles, of whom 5848 were seropositive to T. gondii, were included in this review. Population studies showed that the prevalence of virus infection was most frequent (32%), followed by parasites (18.4%), bacteria (29.7%), and fungi (5.8%). The pooled prevalence of coinfection was found to be 29.1%, with a lower bound of 0.232, an upper bound of 0.350, a standard error of 0.030, and p < 0.001. Heterogeneity (I2) was 99.12%, p < 0.001, with a global variance tau2 = 0.042. Toxoplasma gondii is an opportunist that mainly affects immunocompromised populations. The main coinfections were found to be viral infections, with HIV ranking first, followed by cytomegalovirus, hepatitis B and C, rubella, herpes simplex 1 and 2, SARS-CoV-2, and coxsackie virus.

Keywords:  bacteria; coinfection; parasites; toxoplasmosis; virus

DOI:  https://doi.org/10.3390/microorganisms12102106
Korean J Physiol Pharmacol. 2024 Nov 01. 28(6): 495-501

Precision proteomics with TurboID: mapping the suborganelle landscape.

Han Byeol Kim, Kwang-Eun Kim.

  Recent research underscores the pivotal role of cellular organelles, such as mitochondria, the endoplasmic reticulum, and lysosomes, in maintaining cellular homeostasis. Their dynamic interactions are critical for metabolic regulation and stress response. Analysis of organelle proteomes offers valuable insights into their functions in both physiology and disease. Traditional proteomic approaches to studying isolated organelles are now complemented by innovative methodologies focusing on inter-organelle interactions. This review examines the integration of advanced proximity labeling technologies, including TurboID and split-TurboID, which address the inherent limitations of traditional techniques and enable precision proteomics of suborganelle compartments and inter-organellar contact sites. These innovations have led to discoveries regarding organelle interconnections, revealing mechanisms underlying metabolic processes such as cholesterol metabolism, glucose metabolism, and lysosomal repair. In addition to highlighting the advancements in TurboID applications, this review delineates the evolving trends in organelle research, underscoring the transformative potential of these techniques to significantly enhance organelle-specific proteomic investigations.

Keywords:  Endoplasmic reticulum; Lysosome; Mitochondria; Proteomics

DOI:  https://doi.org/10.4196/kjpp.2024.28.6.495
FEBS Open Bio. 2024 Oct 31.

Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off-target effects.

Kiara E Bornes, Marcus A Moody, Thomas M Huckaba, Megan C Benz, Emily C McConnell, Maryam Foroozesh, Van H Barnes, Bridgette M Collins-Burow, Matthew E Burow, Terry J Watt, Tasha B Toro.

  Lysine deacetylases (KDACs or HDACs) are metal-dependent enzymes that regulate lysine acetylation, a post-translational modification that is present on thousands of human proteins, essential for many cellular processes, and often misregulated in diseases. The selective inhibition of KDACs would allow for understanding of the biological roles of individual KDACs and therapeutic targeting of individual enzymes. Recent studies have suggested that purportedly specific KDAC inhibitors have significant off-target binding, but the biological consequences of off-target binding were not evaluated. We compared the effects of treatment with two of the reportedly most KDAC-selective inhibitors, Tubastatin A and PCI-34051, in HT1080 cells in which the endogenous KDAC6 or KDAC8 gene has been mutated to inactivate enzyme catalysis while retaining enzyme expression. Genetic inactivation results in much stronger deacetylation defects on known targets compared to inhibitor treatment. Gene expression analysis revealed that both inhibitors have extensive and extensively overlapping off-target effects in cells, even at low inhibitor doses. Furthermore, Tubastatin A treatment led to increased histone acetylation, while inactivation of KDAC6 or KDAC8 did not. Genetic inactivation of KDAC6, but not KDAC8, impaired tumor formation in a xenograft model system, in contrast to previous reports with KDAC inhibitors suggesting the reverse. We conclude that the majority of observed biological effects of treatment with KDAC inhibitors are due to off-target effects rather than the intended KDAC inhibition. Developing a truly specific KDAC6 inhibitor could be a promising therapeutic avenue, but it is imperative to develop new inhibitors that selectively mimic genetic inactivation of individual KDACs.

Keywords:  HDAC6; HDAC8; HDACi; RNA‐seq; immunofluorescence

DOI:  https://doi.org/10.1002/2211-5463.13896
Parasit Vectors. 2024 Oct 31. 17(1): 446

Establishment of the auxin inducible degron system for Babesia duncani: a conditional knockdown tool to study precise protein regulation in Babesia spp.

Bo Chen, Qi Zhang, Sen Wang, Xing-Ai Guan, Wan-Xin Luo, Dong-Fang Li, Yue He, Shu-Jing Huang, Ya-Ting Zhou, Jun-Long Zhao, Lan He.

   BACKGROUND: Babesia duncani is a pathogen within the phylum Apicomplexa that causes human babesiosis. It poses a significant threat to public health, as it can be transmitted not only through tick bites but also via blood transfusion. Consequently, an understanding of the gene functions of this pathogen is necessary for the development of drugs and vaccines. However, the absence of conditional gene knockdown tools has hindered the research on this pathogen. The auxin-inducible degron (AID) system is a rapid, reversible conditional knockdown system widely used in gene function studies. Thus, there is an urgent need to establish the AID system in B. duncani to study essential gene functions.
METHODS: The endogenous genes of the Skp1-Cullin-F-box (SCF) complex in B. duncani were identified and confirmed through multiple sequence alignment and conserved domain analysis. The expression of the F-box protein TIR1 from Oryza sativa (OsTIR1) was achieved by constructing a transgenic parasite strain using a homologous recombination strategy. Polymerase chain reaction (PCR), western blot, and indirect immunofluorescence assay (IFA) were used to confirm the correct monoclonal parasite strain. The degradation of enhanced green fluorescent protein (eGFP) tagged with an AID degron was detected through western blot and live-cell fluorescence microscopy after treatment of indole-3-acetic acid (IAA).
RESULTS: In this study, Skp1, Cul1, and Rbx1 of the SCF complex in B. duncani were identified through sequence alignment and domain analysis. A pure BdTIR1 strain with expression of the OsTIR1 gene was constructed through homologous recombination and confirmed. This strain showed no significant differences from the wild type (WT) in terms of growth rate and proportions of different parasite forms. The eGFP tagged with an AID degron was successfully induced for degradation using 500 μM IAA. Grayscale analysis of western blot indicated a 61.3% reduction in eGFP expression levels, while fluorescence intensity analysis showed a 77.5% decrease in fluorescence intensity. Increasing the IAA concentration to 2 mM accelerated eGFP degradation and enhanced the extent of degradation.
CONCLUSIONS: This study demonstrated the functionality of the AID system in regulating protein levels by inducing rapid degradation of eGFP using IAA, providing an important research tool for studying essential gene functions related to invasion, egress, and virulence of B. duncani. Moreover, it also offers a construction strategy for apicomplexan parasites that have not developed an AID system.

Keywords:   Babesia duncani ; Auxin-inducible degron; Conditional knockdown system; Protein degradation

DOI:  https://doi.org/10.1186/s13071-024-06458-4
Anal Biochem. 2024 Oct 24. pii: S0003-2697(24)00242-2. [Epub ahead of print]696 115698

An ATP detection system based on the enzyme reaction with biotin protein ligase.

Shinji Sueda, Satoshi Fujii.

  Adenosine triphosphate (ATP) is the energy currency of all living organisms and can be used as an indicator for cell proliferation and cytotoxicity. In the present work, we have developed a novel ATP detection system by combining the biotinylation reaction from archaeon Sulfolobus tokodaii with fluorescence resonance energy transfer (FRET). In biotinylation from S. tokodaii, an enzyme known as biotin protein ligase (BPL) forms a very stable complex with its product, biotinylated substrate protein (BCCP). Here, BPL and BCCP were fused to the fluorescent proteins Cerulean and Clover, respectively, and ATP detection was accomplished by monitoring the FRET signal between the two fluorescent proteins, since ATP is an essential component for biotinylation and the tight BPL-BCCP complex is formed only after biotinylation. Using this system, we have succeeded in detecting 5 nM of ATP by biotinylation reaction with 50 nM of each fusion protein. Our method has a characteristic that the signal does not decay for at least 2 h after the start of the reaction, unlike in the case of the luminescence-based assay with luciferase commonly used for the ATP detection. Thus, our system allows for ATP detection which is not significantly constrained by measurement timing.

Keywords:  ATP detection; Biotinylation; Enzyme reaction; FRET; Fluorescent protein

DOI:  https://doi.org/10.1016/j.ab.2024.115698
Chembiochem. 2024 Oct 27. e202400639

Cracking Lysine Crotonylation (Kcr): Enlightening a Promising Post-Translational Modification.

Marinda Westerveld, Kosta Besermenji, David Aidukas, Nikita Ostrovitsa, Rita Petracca.

  Lysine crotonylation (Kcr) is a recently discovered post-translational modification (PTM). Both histone and non-histone Kcr-proteins have been associated with numerous diseases including cancer, acute kidney injury, HIV latency, and cardiovascular disease. Histone Kcr enhances gene expression to a larger extend than the extensively studied lysine acetylation (Kac), suggesting Kcr as a novel potential therapeutic target. Although numerous scientific reports on crotonylation were published in the last years, relevant knowledge gaps concerning this PTM and its regulation still remain. To date, only few selective Kcr-interacting proteins have been identified and selective methods for the enrichment of Kcr-proteins in chemical proteomics analysis are still lacking. The development of new techniques to study this underexplored PTM could then clarify its function in health and disease and hopefully accelerate the development of new therapeutics for Kcr-related disease. Herein we briefly review what is known about the regulation mechanisms of Kcr and the current methods used to identify Kcr-proteins and their interacting partners. This report aims to highlight the significant potential of Kcr as a therapeutic target and to identify the existing scientific gaps that new research must address.

Keywords:  Chemical proteomics; Crotonyl-CoA; Enzymatic PTMs regulation; Post-translational modifications (PTMs)

DOI:  https://doi.org/10.1002/cbic.202400639
Open Biol. 2024 Oct;14(10): 240209

The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.

Murielle M Morales, Matthew R Pratt.

  Cells must rapidly adapt to changes in nutrient conditions through responsive signalling cascades to maintain homeostasis. One of these adaptive pathways results in the post-translational modification of proteins by O-GlcNAc. O-GlcNAc modifies thousands of nuclear and cytoplasmic proteins in response to nutrient availability through the hexosamine biosynthetic pathway. O-GlcNAc is highly dynamic and can be added and removed from proteins multiple times throughout their life cycle, setting it up to be an ideal regulator of cellular processes in response to metabolic changes. Here, we describe the link between cellular metabolism and O-GlcNAc, and we explore O-GlcNAc's role in regulating cellular processes in response to nutrient levels. Specifically, we discuss the mechanisms of elevated O-GlcNAc levels in contributing to diabetes and cancer, as well as the role of decreased O-GlcNAc levels in neurodegeneration. These studies form a foundational understanding of aberrant O-GlcNAc in human disease and provide an opportunity to further improve disease identification and treatment.

Keywords:  O-GlcNAc; metabolism; modifications; post-translational; regulators; sensor

DOI:  https://doi.org/10.1098/rsob.240209
Int J Mol Sci. 2024 Oct 12. pii: 10982. [Epub ahead of print]25(20):

Acetylation of Histone H3 in Cancer Progression and Prognosis.

Paulina Miziak, Marzena Baran, Lidia Borkiewicz, Tomasz Trombik, Andrzej Stepulak.

  Cancer is a multifactorial disease resulting from both genetic factors and epigenetic changes. Histone acetylation, a post-translational modification, which alters chromatin architecture and regulates gene expression is associated with cancer initiation, development and progression. Aberrations in global histone acetylation levels are observed in various cancer cells and are also associated with patients' tumor aggressiveness. Therefore, histone acetylation may have prognostic utility and serve as a potential biomarker of cancer progression and patients' prognosis. The reversible modification of histones by an acetyl group is versatile. One particular histone can be acetylated on different lysine residues, subsequently resulting in different biological outcomes. Here, we discuss recent findings on the acetylation of the highly conserved histone protein H3 in the context of cancer biology. Specifically, we review the acetylation of particular H3 residues in various cancer types. We further highlight the significance of H3 acetylation levels as a potential cancer biomarker with prognostic implications.

Keywords:  biomarker; cancer; cancer prognosis; cancer progression; histone H3; histone acetylation

DOI:  https://doi.org/10.3390/ijms252010982