bims-toxgon 2024-12-29 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2024–12–29
27 papers selected by
Lakesh Kumar, BITS Pilani

A Novel Nuclear Protein Complex Controlling the Expression of Developmentally Regulated Genes in Toxoplasma Gondii.
Autophagy protein Atg7 is essential for maintaining malaria parasite cellular homeostasis and organelle biogenesis.
Pathological mechanisms of glial cell activation and neurodegenerative and neuropsychiatric disorders caused by Toxoplasma gondii infection.
Vaccination with a DNA vaccine cocktail encoding TgROP2, TgROP5, TgROP9, TgROP16, TgROP17, and TgROP18 confers limited protection against Toxoplasma gondii in BALB/c mice.
Bending stiffness of Toxoplasma gondii actin filaments.
CD4 Co-Receptor Regulates Sex-Specific NK Cell Responses to Acute Toxoplasma gondii Infection.
Evaluation of the toxoplasma Urm1 gene deletion mutant (PruΔUrm1) as a promising vaccine candidate against toxoplasmosis in mice.
V-ATPase in cancer: mechanistic insights and therapeutic potentials.
HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses.
Oscillatory autophagy induction is enabled by an updated AMPK-ULK1 regulatory wiring.
Synthetic approaches and clinical applications of representative HDAC inhibitors for cancer therapy: A review.
Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.
Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier.
Hydrolysis of the acetyl-CoA allosteric activator by Staphylococcus aureus pyruvate carboxylase.
Reciprocal regulation between bacterial secretion systems and host metabolism: Enhancing bacterial intracellular survival capability.
Acetylation-Mediated Post-Translational Modification of Pyruvate Dehydrogenase Plays a Critical Role in the Regulation of the Cellular Acetylome During Metabolic Stress.
HDAC10 switches NLRP3 modification from acetylation to ubiquitination and attenuates acute inflammatory diseases.
Characterization of acidic lysine acylations in mycobacteria.
Inositol phosphates dynamically enhance stability, solubility and catalytic activity of mTOR.
N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine.
Structure-based design of covalent nanobody binders for a thermostable green fluorescence protein.
Limitations in quantum metrology approaches to imaging resolution.
Structural and biochemical characterization of a zinc metallopeptidase from Porphyromonas gingivalis.
Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
Cost-effective and simple flow cytometry quantification of receptor-mediated autophagy using fluorescent tagging.
Phosphoinositide signaling in the nucleus: Impacts on chromatin and transcription regulation.
Regulation of autophagy and cellular signaling through non-histone protein methylation.

Adv Sci (Weinh). 2024 Dec 24. e2412000

A Novel Nuclear Protein Complex Controlling the Expression of Developmentally Regulated Genes in Toxoplasma Gondii.

Lilan Xue, Jingwen Zhang, Lihong Zhang, Fuqiang Fan, Xiaoyan Yin, Hengrui Tian, Bang Shen.

  Toxoplasma gondii is a ubiquitous protozoan parasite with a complex life cycle containing multiple developmental stages. The parasites have distinct gene expression patterns at different stages to enable stage specific life activities, but the underlying regulatory mechanisms are largely unknown. In this study, a nuclear complex is identified that controls the expression of developmentally regulated genes. This complex consists of the AP2 family transcription factor AP2XII-5, the epigenetic factors MORC and HDAC3, as well as a novel AP2XII-5 interacting protein 1 (AIP1) that stabilizes this complex. At the tachyzoite stage when the parasites proliferate rapidly by asexual endodyogeny, AP2XII-5 binds to the promoter regions of developmentally activated genes and recruits MORC and HDAC3 to suppress their expression. When sexual commitment and merozoite development are triggered, the abundance of AP2XII-5 decreases and its suppression on target genes is relieved. In contrast to MORC and HDAC3, which regulate Toxoplasma development but are also essential for tachyzoite growth, AP2XII-5 and AIP1 are dispensable for tachyzoite proliferation in vitro. These data suggest that while MORC and HDAC3 have broad regulatory activities, forming a complex with AP2XII-5 and AIP1 enables them to specifically regulate gene expression during development.

Keywords:  AP2 transcription factor; HDAC3; bradyzoite; epigenetic factor; merozoite

DOI:  https://doi.org/10.1002/advs.202412000
mBio. 2024 Dec 23. e0273524

Autophagy protein Atg7 is essential for maintaining malaria parasite cellular homeostasis and organelle biogenesis.

Akancha Mishra, Suryansh Rajput, Pratik Narain Srivastava, H Shabeer Ali, Satish Mishra.

  Plasmodium parasites have a complex life cycle that transitions between mosquito and mammalian hosts, and undergo continuous cellular remodeling to adapt to various drastic environments. Following hepatocyte invasion, the parasite discards superfluous organelles for intracellular replication, and the remnant organelles undergo extensive branching and mature into hepatic merozoites. Autophagy is a ubiquitous eukaryotic process that permits the recycling of intracellular components. Here, we show that the Plasmodium berghei autophagy-related E1-like enzyme Atg7 is expressed in the blood, sporozoites, and liver stages, localized to the parasite cytosol, and is essential for the localization of Atg8 on the membrane and the development of parasite blood and liver forms. We found that depleting Atg7 abolishes Atg8 lipidation, exocytosis of micronemes, organelle biogenesis, and the formation of merozoites during liver-stage development. Overall, this study establishes the essential functions of Atg7 in Plasmodium blood and liver stages, and highlights its role in maintaining the parasite's cellular homeostasis and organelle biogenesis.IMPORTANCEThe malaria life cycle involves two hosts, mosquitoes and vertebrates. Plasmodium parasites undergo complex intracellular and extracellular stages during this transition. Here, we report that an autophagy-related E1-like enzyme Atg7 is required to conjugate Atg8 on the apicoplast membrane. Atg7 depletion in Plasmodium berghei resulted in the loss of Atg8 lipidation and multiple defects like clearance of micronemes, organelle biogenesis, and maturation of hepatic schizonts during liver-stage development. The essentiality of Plasmodium Atg7 in blood and liver stages suggests it is a prospective target for developing autophagy-specific inhibitors. These results highlight the importance of autophagy in malaria parasite development.

Keywords:  Atg7; Atg8; ER; Plasmodium; apicoplast; autophagy; liver stage; malaria; sporozoites

DOI:  https://doi.org/10.1128/mbio.02735-24
Front Microbiol. 2024 ;15 1512233

Pathological mechanisms of glial cell activation and neurodegenerative and neuropsychiatric disorders caused by Toxoplasma gondii infection.

Zihan Yang, Jiating Chen, Chi Zhang, Hongjuan Peng.

  Toxoplasma gondii is an intracellular opportunistic parasite that exists in a latent form within the human central nervous system (CNS), even in immune-competent hosts. During acute infection, T. gondii traverses the blood-brain barrier (BBB). In the subsequent chronic infection phase, the infiltration of immune cells into the brain, driven by T. gondii infection and the formation of parasitic cysts, leads to persistent activation and proliferation of astrocytes and microglia. This process results in neuronal damages that are fatal in some cases. Through inducing systemic immune responses, T. gondii infection can dramatically alter the behavior of rodents and increase the risk of various neuropsychiatric disorders in humans. In this review, we explore some recent research progress on the major events involved in BBB disruption, glial cell activation and neuronal damage following T. gondii infection in hosts. It further discusses potential pathological mechanisms and the feasible treatment approaches for the neurodegenerative and neuropsychiatric disorders caused by T. gondii infection to extend our understanding for pathogenesis and preventive control of toxoplasmosis in humans.

Keywords:  Toxoplasma gondii; blood–brain barrier; glial cell activation; neuronal damage; neuropsychiatric disorders

DOI:  https://doi.org/10.3389/fmicb.2024.1512233
Parasitol Res. 2024 Dec 26. 123(12): 420

Vaccination with a DNA vaccine cocktail encoding TgROP2, TgROP5, TgROP9, TgROP16, TgROP17, and TgROP18 confers limited protection against Toxoplasma gondii in BALB/c mice.

Rongqi Du, Jinling He, Jiali Meng, Dongchao Zhang, Danruo Li, Hui Wang, Aili Fan, Gang Xu, Shuhui Ma, Zonghui Zuo, Qiqi Song, Tianming Jin.

  Toxoplasmosis is a foodborne zoonotic parasitic disease caused by Toxoplasma gondii, which seriously threatens to human health and causes economic losses. At present, there is no effective vaccine strategy for the prevention and control of toxoplasmosis. T. gondii rhoptry proteins (ROPs) are important proteins secreted by the parasite during the early stage of invasion into host cells. In this study, we constructed six individual plasmids (pVAX1-ROP2, pVAX1-ROP5, pVAX1-ROP9, pVAX1-ROP16, pVAX1-ROP17, and pVAX1-ROP18) encoding T. gondii rhoptry proteins and then used an equimolar amount of each as a vaccine cocktail. Following booster immunization, serum antibody levels, splenic lymphocyte proliferation, cytokine production, and survival time after infection with T. gondii RH strain were measured in immunized mice. The results showed that the mice immunized with the DNA vaccine cocktail developed a higher level of the specific anti-T. gondii IgG in serum and the cytokines such as IFN-γ, IL-2, IL-12, and IL-4 (P < 0.01). The stimulation index (SI) of spleen lymphocytes (P < 0.01), the frequencies of CD4+ T lymphocytes (P < 0.01), and the ratio of CD4+/CD8+ T lymphocytes (P < 0.05 or P < 0.01) in the vaccine-immunized mice were significantly increased compared to the control group. After challenge with the virulent T. gondii RH strain tachyzoites, the survival time of mice in the DNA vaccine cocktail group (18.1 ± 1.81 d) was significantly longer (P < 0.01) than that in the control group (8.4 ± 1.02 or 7.9 ± 0.83 d). The results indicated that the DNA vaccine cocktail could elicit strong humoral and cellular immune responses in mice and could also improve the resistance of mice to acute T. gondii infection.

Keywords:   Toxoplasma gondii ; DNA vaccine; Protective immunity; Rhoptry proteins

DOI:  https://doi.org/10.1007/s00436-024-08435-3
J Biol Chem. 2024 Dec 18. pii: S0021-9258(24)02603-6. [Epub ahead of print] 108101

Bending stiffness of Toxoplasma gondii actin filaments.

Wenxiang Cao, Thomas E Sladewski, Aoife T Heaslip, Enrique M De La Cruz.

Actin is essential for the survival and pathogenicity of the Apicomplexan parasite Toxoplasma gondii, where it plays essential functions in cargo transport, invasion, egress, and organelle inheritance. Recent work has shown that, unlike vertebrate skeletal muscle actin, purified T. gondii actin filaments (TgAct1) can undergo rapid treadmilling, due to large differences in the barbed- and pointed-end critical concentrations, rapid subunit dissociation from filament ends, and a rapid nucleotide exchange rate constant from free monomers. Previous structural analysis suggested that the unique assembly properties of TgAct1filaments may be a functional consequence of reduced contacts between the DNAse-1 binding loop (D-loop) of a filament subunit and its adjacent, long-axis subunit neighbor. Because the D-loop makes stabilizing interactions between neighboring subunits, it has been implicated in regulating the mechanical properties of actin filaments. In this study, we measured the bending persistence length (LB) of TgAct1 filaments and the filament length distribution. We found that despite compromised intersubunit D-loop contacts, TgAct1 filaments have similar bending stiffness and thermodynamic stability as vertebrate actin filaments. Analysis of published cryoEM image density maps indicates that TgAct1 filaments retain a stabilizing inter-subunit salt bridge between E168 and K62 and reveals visible density between Y167 and S61 of adjacent filament subunits, consistent with a conserved cation binding site proximal to the D-loop, as initially identified in vertebrate skeletal muscle actin filaments. These results favor a mechanism in which weak D-loop interactions compromise TgAct1 subunit incorporation at filament ends, while minimally affecting overall subunit interactions within filaments.

DOI: https://doi.org/10.1016/j.jbc.2024.108101
bioRxiv. 2024 Dec 12. pii: 2024.12.06.627254. [Epub ahead of print]

CD4 Co-Receptor Regulates Sex-Specific NK Cell Responses to Acute Toxoplasma gondii Infection.

Tathagato Roy, Leah Bernstein, Hunter K Keplinger, Kaatje Fisk, Sai K Ng, Stephen L Denton, Jason P Gigley.

Immunity to Toxoplasma gondii ( T. gondii ) is sexually dimorphic in humans and mice, with females having higher morbidity and mortality during immune dysfunction and HIV-AIDS. The mechanisms underlying these sex differences are unclear. We investigated how a lack of CD4+ T cells (CD4 co-receptor KO) impacted T. gondii survival in mice. Female CD4 co-receptor KO mice succumbed to T. gondii much faster than males. To dissect why female CD4 co-receptor KO mice died faster, we tested their NK cell responses to acute T. gondii infection compared to males. Although in wild-type (WT) animals, both sexes had similar increases in total NK cells and IFNγ + NK cells, infected CD4 co-receptor KO female mice had 50% fewer IFNγ+ NK cells than infected WT female mice. Infected male CD4 co-receptor KO had a similar increase in IFNγ+ NK cells as WT male mice. Since CD4 co-receptor deficient mice still have functional helper T cells that are CD4-, we next tested survival and NK cell responses in female and male MHCII deficient (MHCIIKO) animals, which completely lack helper CD4+T cells. Surprisingly, survival, NK cell numbers, and IFNγ+ NK cells were not significantly different between WT or MHCIIKO female and male mice. These results suggest CD4 co-receptor expression is required for survival via optimal NK cell responses during acute T. gondii infection only in female mice and not in male mice. Our findings reveal an unappreciated sexual dimorphic role of CD4 co-receptor expression in regulating NK cell responses to acute T. gondii infection.

DOI: https://doi.org/10.1101/2024.12.06.627254
Vaccine. 2024 Dec 19. pii: S0264-410X(24)01314-8. [Epub ahead of print]45 126632

Evaluation of the toxoplasma Urm1 gene deletion mutant (PruΔUrm1) as a promising vaccine candidate against toxoplasmosis in mice.

Shu Bian, Qingxiu Cai, Shujing Wang, Ying Xie, Nianyuan Chen, Qingyang Song, Hongmei Li, Ningning Zhao, Xiao Zhang.

  Toxoplasmosis is a significant zoonotic disease that poses a serious threat to both human and animal health. Despite ongoing research, developing an effective vaccine for toxoplasmosis remains a challenge. In this study, we evaluated the vaccine potential of the Toxoplasma Urm1 gene deletion mutant (PruΔUrm1) by assessing its pathogenicity and protective efficacy in mice. Using CRISPR/Cas9 technology, we successfully created a type II Toxoplasma gondii Pru mutant strain with a deleted Urm1 gene. Compared to the wild-type parasite, the PruΔUrm1 strain exhibited significantly reduced invasive and proliferative abilities in vitro. In in vivo studies, mice intraperitoneally infected with the parental Pru strain showed severe symptoms including emaciation, hunching, and high mortality rates. In contrast, mice infected with PruΔUrm1 tachyzoites demonstrated a 100 % survival rate, no overt symptoms, and a markedly reduced parasite burden in the liver, spleen, and lungs, indicating reduced pathogenicity. Notably, PruΔUrm1 vaccination triggered a strong immune response, characterized by significantly elevated cytokine levels, including TNF-α, IFN-γ and IL-10. Furthermore, we assessed the immunoprotective efficacy of PruΔUrm1 vaccination in mice against type I strains. Mice immunized with PruΔUrm1 were able to resist the tachyzoites of type I RH wild-type parasites, achieving a 100 % survival rate and significantly reduced parasite loads in the liver, spleen and lungs. These data demonstrate that PruΔUrm1 immunization provides effective protection against acute Toxoplasma infections and holds promise as a potential vaccine candidate for toxoplasmosis.

Keywords:  Gene knockout; Immune protection; Live-attenuated vaccine; Toxoplasma gondii; Urm1

DOI:  https://doi.org/10.1016/j.vaccine.2024.126632
Cell Commun Signal. 2024 Dec 20. 22(1): 613

V-ATPase in cancer: mechanistic insights and therapeutic potentials.

Tingting Chen, Xiaotan Lin, Shuo Lu, Bo Li.

  Vacuolar-type H+-ATPase (V-ATPase) is a crucial proton pump that plays an essential role in maintaining intracellular pH homeostasis and a variety of physiological processes. This review provides an in-depth exploration of the structural components, functional mechanisms, and regulatory modes of V-ATPase in cancer cells. Comprising two main domains, V1 and V0, V-ATPase drives the proton pump through ATP hydrolysis, sustaining the pH balance within the cell and organelles. In cancer cells, the enhanced activity of V-ATPase is closely associated with the proliferation and metastasis of tumor cells, and it promotes the growth and invasion of tumor cells by regulating pH values in the tumor microenvironment. Moreover, the interaction between V-ATPase and key metabolic regulatory factors, the mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), impacts the metabolic state of cancer cells. The role of V-ATPase in tumor drug resistance and its regulatory mechanism in non-canonical autophagy offer new perspectives and potential targets for cancer therapy. Future research directions will focus on the specific mechanisms of action of V-ATPase in the tumor microenvironment and how to translate its inhibitors into clinical applications, providing significant scientific evidence for the development of new therapeutic strategies.

Keywords:  Proton pump; Therapeutic targets; V-ATPase; pH homeostasis

DOI:  https://doi.org/10.1186/s12964-024-01998-9
bioRxiv. 2024 Dec 11. pii: 2024.12.10.627820. [Epub ahead of print]

HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses.

Hannah Lohner, Xiao Han, Junling Ren, Shuang Liang, Ruqiang Liang, Huizhi Wang.

Post-translational modifications (PTMs) are critical regulators of protein function and cellular signaling. While histone deacetylation by histone deacetylases (HDACs) is well established, the role of specific HDACs in modulating non-histone protein PTMs, particularly in an infectious context, is poorly understood. Here, we reveal a pivotal role for HDAC6 in orchestrating periodontal inflammation through its dual regulatory effects on FoxO1 acetylation and phosphorylation. Using Porphyromonas gingivalis , a key periodontal pathogen, as a model pathogen, we observed that infection induces HDAC6 activation, driving inflammatory responses via modulating FoxO1 activity. HDAC6 depletion increased FoxO1 acetylation and phosphorylation, leading to its cytoplasmic sequestration and subsequent suppression of FoxO1- mediated pro-inflammatory cytokine production in macrophages. Mechanistically, HDAC6 deficiency not only directly enhances the acetylation of FoxO1 but also upregulates the expression of Rictor, a critical component of the mTORC2 complex, thereby promoting Akt phosphorylation and subsequently FoxO1 phosphorylation. This results in its cytoplasmic retention and attenuated inflammatory transcriptional activity. Functional studies demonstrated that HDAC6 depletion suppressed the production of key inflammatory mediators, including TNFα, IL-6, IL-12p40, and MIP-2, while promoting macrophage polarization toward anti-inflammatory M2 phenotypes. In vivo , using oral gavage infection and ligature-induced mouse periodontitis models, HDAC6 deficiency significantly reduced inflammatory cell infiltration in gingival tissues and protected against alveolar bone loss. These findings establish HDAC6 as a central regulator of periodontal inflammation, acting through the coordinated modulation of FoxO1 acetylation and phosphorylation. Beyond its role in oral pathology, HDAC6 may serve as a promising therapeutic target for managing inflammatory diseases linked to immune dysregulation.

DOI: https://doi.org/10.1101/2024.12.10.627820
PLoS One. 2024 ;19(12): e0313302

Oscillatory autophagy induction is enabled by an updated AMPK-ULK1 regulatory wiring.

Orsolya Kapuy, Marianna Holczer, Luca Csabai, Tamás Korcsmáros.

Autophagy-dependent survival relies on a crucial oscillatory response during cellular stress. Although oscillatory behaviour is typically associated with processes like the cell cycle or circadian rhythm, emerging experimental and theoretical evidence suggests that such periodic dynamics may explain conflicting experimental results in autophagy research. In this study, we demonstrate that oscillatory behaviour in the regulation of the non-selective, stress-induced macroautophagy arises from a series of interlinked negative and positive feedback loops within the mTORC1-AMPK-ULK1 regulatory triangle. While many of these interactions have been known for decades, recent discoveries have revealed how mTORC1, AMPK, and ULK1 are truly interconnected. Although these new findings initially appeared contradictory to established models, additional experiments and our systems biology analysis clarify the updated regulatory structure. Through computational modelling of the autophagy oscillatory response, we show how this regulatory network governs autophagy induction. Our results not only reconcile previous conflicting experimental observations but also offer insights for refining autophagy regulation and advancing understanding of its mechanisms of action.

DOI: https://doi.org/10.1371/journal.pone.0313302
Eur J Med Chem. 2024 Dec 19. pii: S0223-5234(24)01067-5. [Epub ahead of print]283 117185

Synthetic approaches and clinical applications of representative HDAC inhibitors for cancer therapy: A review.

Zhengming Lv, Tianyi Ji, Jie Liu, Xu Sun, Huimin Liang.

  Histone deacetylase (HDAC) inhibitors are a promising class of epigenetic modulators in cancer therapy. This review provides a comprehensive analysis of recent synthetic strategies and clinical applications of key HDAC inhibitors for oncology. HDACs play a critical role in modulating chromatin structure and gene expression by removing acetyl groups from histone proteins, leading to transcriptional repression of tumor suppressor genes. By inhibiting HDAC activity, HDAC inhibitors restore normal acetylation patterns, reactivating silenced tumor suppressor genes and inducing cell cycle arrest, apoptosis, and autophagy in cancer cells. The review explores synthetic approaches to developing representative HDAC inhibitors that have been approved or in various clinical trials. Through an integrated perspective on the synthesis, mechanism of action, and clinical advancements of HDAC inhibitors, this review aims to guide future research toward next-generation HDAC inhibitors that could enhance cancer treatment efficacy while minimizing toxicity, offering insights for chemists and clinicians in the field of oncology.

Keywords:  Cancer therapy; Clinical applications; HDAC; Synthetic approaches

DOI:  https://doi.org/10.1016/j.ejmech.2024.117185
Metabolites. 2024 Dec 13. pii: 703. [Epub ahead of print]14(12):

Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.

Natalia V Beloborodova, Nadezhda I Fedotcheva.

   BACKGROUND: Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied.
METHODS: In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods.
RESULTS: It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5-1 mM decreased the respiratory control and the swelling rate by 20-30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor.
CONCLUSIONS: The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions.

Keywords:  acetyl phosphate; adenine nucleotide translocase; alkalization; mitochondrial permeability transition pore; nonenzymatic acetylation; respiration; succinate dehydrogenase

DOI:  https://doi.org/10.3390/metabo14120703
Eur J Med Chem. 2024 Dec 11. pii: S0223-5234(24)01032-8. [Epub ahead of print]283 117150

Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier.

Lingaiah Maram, Jessica M Michael, Henry Politte, Vaishnavi S Srirama, Aymen Hadji, Mohammad Habibi, Meredith O Kelly, Rita T Brookheart, Brian N Finck, Lamees Hegazy, Kyle S McCommis, Bahaa Elgendy.

Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties. To address this, approximately 50 pyrazole-based MPC inhibitors were synthesized to explore the structure-activity relationship for MPC inhibition, evaluated through inhibition of mitochondrial pyruvate respiration. These inhibitors were designed with increased steric hindrance around electron-deficient double bonds, allowing for refined structural modifications that reduce their potential to act as Michael acceptors. Additionally, the new MPC inhibitors directly inhibited stellate cell activation, indicating their potential as therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Unlike the thiazolidinedione class of MPC inhibitors, these compounds did not activate the nuclear receptor PPARγ. Molecular modeling was conducted to explore interactions between these novel inhibitors and the MPC complex. We have identified the chemical determinants critical for MPC inhibition and successfully developed novel inhibitors that are potent, specific and possess excellent physicochemical properties, high solubility, and outstanding metabolic stability in human liver microsomes.

DOI: https://doi.org/10.1016/j.ejmech.2024.117150
Arch Biochem Biophys. 2024 Dec 24. pii: S0003-9861(24)00402-8. [Epub ahead of print] 110280

Hydrolysis of the acetyl-CoA allosteric activator by Staphylococcus aureus pyruvate carboxylase.

Amanda J Laseke, Jeremy R Lohman, Martin St Maurice.

  Pyruvate carboxylase (PC) catalyzes the carboxylation of pyruvate to oxaloacetate which serves as an important anaplerotic reaction to replenish citric acid cycle intermediates. In most organisms, the PC-catalyzed reaction is allosterically activated by acetyl-coenzyme A. It has previously been reported that vertebrate PC can catalyze the hydrolysis of acetyl-CoA, offering a potential means for the enzyme to attenuate its allosteric activation. However, in the years since this initial report, there has been no further investigation of this phenomenon. The allosteric binding site for acetyl-CoA is now well characterized, enabling more detailed studies on acetyl-CoA hydrolysis at the allosteric site. Here, we confirm that slow acetyl-CoA hydrolysis is catalyzed by a bacterial PC from Staphylococcus aureus, indicating that this phenomenon is a broad feature of PC enzymes spanning the domains of life. Surprisingly, the enzyme can hydrolyze acetyl-CoA even when the binding site for the acetyl moiety is eliminated through truncation of the biotin carboxylase domain. This suggests that an alternative site for acetyl-CoA binding and hydrolysis may be present in the carboxyltransferase domain of S. aureus PC. We conclude that PC has evolved to minimize the rate of acetyl-CoA hydrolysis at the allosteric site and update the description of PC-catalyzed acetyl-CoA hydrolysis to suggest that this reaction is unlikely to play a significant physiological, metabolic or catalytic role.

Keywords:  acetyl-coenzyme A; allostery; anaplerosis; biotin; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.abb.2024.110280
Microbiol Res. 2024 Dec 16. pii: S0944-5013(24)00426-9. [Epub ahead of print]292 128025

Reciprocal regulation between bacterial secretion systems and host metabolism: Enhancing bacterial intracellular survival capability.

Lina Zhan, Jiongchen Ge, Lin Xia, Ying Zhang.

  Secretion systems are intricate nanomachines present on many bacterial cell membranes that deliver various bacterially-encoded effector proteins into eukaryotic or prokaryotic cells. They are pivotal in bacterial invasion, host colonization, and pathogenesis. After infection, bacteria employ these machines to deliver toxic effectors to the cytoplasm of host cells that disrupt their metabolic balance, such as interfering with glucose metabolism, promoting lipid droplets formation, altering amino acid profiles and mitochondrial morphology, and reducing ROS levels, to ensure bacterial intracellular survival. Furthermore, metabolites within host cells can modulate the expression and/or function of bacterial secretion systems. This review summarizes recent advancements in understanding the impact of bacterial secretion systems on host cell metabolism and the feedback regulation of host metabolites on these machines, providing novel perspectives on host-pathogen interactions and mechanisms of bacterial pathogenesis.

Keywords:  Bacterial secretion systems; Glycolysis; Host metabolism; Lipid droplets; Mitochondria

DOI:  https://doi.org/10.1016/j.micres.2024.128025
Metabolites. 2024 Dec 12. pii: 701. [Epub ahead of print]14(12):

Acetylation-Mediated Post-Translational Modification of Pyruvate Dehydrogenase Plays a Critical Role in the Regulation of the Cellular Acetylome During Metabolic Stress.

Aishwarya Rajakumar, Sarah Nguyen, Nicole Ford, Gbenga Ogundipe, Ethan Lopez-Nowak, Olena Kondrachuk, Manish K Gupta.

  Background: Cardiac diseases remain one of the leading causes of death globally, often linked to ischemic conditions that can affect cellular homeostasis and metabolism, which can lead to the development of cardiovascular dysfunction. Considering the effect of ischemic cardiomyopathy on the global population, it is vital to understand the impact of ischemia on cardiac cells and how ischemic conditions change different cellular functions through post-translational modification of cellular proteins. Methods: To understand the cellular function and fine-tuning during stress, we established an ischemia model using neonatal rat ventricular cardiomyocytes. Further, the level of cellular acetylation was determined by Western blotting and affinity chromatography coupled with liquid chromatography-mass spectroscopy. Results: Our study found that the level of cellular acetylation significantly reduced during ischemic conditions compared to normoxic conditions. Further, in mass spectroscopy data, 179 acetylation sites were identified in the proteins in ischemic cardiomyocytes. Among them, acetylation at 121 proteins was downregulated, and 26 proteins were upregulated compared to the control groups. Differentially, acetylated proteins are mainly involved in cellular metabolism, sarcomere structure, and motor activity. Additionally, a protein enrichment study identified that the ischemic condition impacted two major biological pathways: the acetyl-CoA biosynthesis process from pyruvate and the tricarboxylic acid cycle by deacetylation of the associated proteins. Moreover, most differential acetylation was found in the protein pyruvate dehydrogenase complex. Conclusions: Understanding the differential acetylation of cellular protein during ischemia may help to protect against the harmful effect of ischemia on cellular metabolism and cytoskeleton organization. Additionally, our study can help to understand the fine-tuning of proteins at different sites during ischemia.

Keywords:  acetylation; cardiomyocytes; ischemia; metabolism; mitochondria; post-translational modification; pyruvate dehydrogenase complex; ryanodine receptor 3

DOI:  https://doi.org/10.3390/metabo14120701
Cell Commun Signal. 2024 Dec 20. 22(1): 615

HDAC10 switches NLRP3 modification from acetylation to ubiquitination and attenuates acute inflammatory diseases.

Min Yang, Zhenzhi Qin, Yueke Lin, Dapeng Ma, Caiyu Sun, Haocheng Xuan, Xiuling Cui, Wei Ma, Xinyi Zhu, Lihui Han.

   BACKGROUND: The NOD-like receptor protein (NLRP)3 inflammasome is at the signaling hub center to instigate inflammation in response to pathogen infection or oxidative stress, and its tight control is pivotal for immune defense against infection while avoiding parallel intensive inflammatory tissue injury. Acetylation of NLRP3 is critical for the full activation of NLRP3 inflammasome, while the precise regulation of the acetylation and deacetylation circuit of NLRP3 protein remained to be fully understood.
METHODS: The interaction between histone deacetylase 10 (HDAC10) and NLRP3 was detected by immunoprecipitation and western blot in the HDAC10 and NLRP3 overexpressing cells. The role of HDAC10 in NLRP3 inflammasome activation was measured by immunofluorescence, real-time PCR and immunoblotting assay in peritoneal macrophages and bone marrow-derived macrophages after the stimulation with LPS and ATP. To investigate the role of HDAC10 in NLRP3-involved inflammatory diseases, the Hdac10 knockout (Hdac10-/-) mice were used to construct the LPS-induced acute endotoxemia model and folic acid-induced acute tubular necrosis model. Tissue injury level was analyzed by hematoxylin and eosin staining, and the serum level of IL-1β was measured by enzyme-linked immunosorbent assay (ELISA). The conservative analysis and immunoprecipitation assay were performed to screen the precise catalytic site regulated by HDAC10 responsible for the switching from the acetylation to ubiquitination of NLRP3.
RESULTS: Here we demonstrated that HDAC10 directly interacted with NLRP3 and induced the deacetylation of NLRP3, thus leading to the inhibition of NLRP3 inflammasome and alleviation of NLRP3 inflammasome-mediated acute inflammatory injury. Further investigation demonstrated that HDAC10 directly induced the deacetylation of NLRP3 at K496 residue, thus switching NLRP3 acetylation to the ubiquitination modification, resulting in the proteasomal degradation of NLRP3 protein. Thus, this study identified HDAC10 as a new eraser for NLRP3 acetylation, and HDAC10 attenuated NLRP3 inflammasome involved acute inflammation via directly deacetylating NLRP3.
CONCLUSIONS: This study indicated that HDAC10 switched NLRP3 modification from acetylation to ubiquitination and attenuated acute inflammatory diseases, thus it provided a potential therapeutic strategy for NLRP3 inflammasome-associated diseases by targeting HDAC10.

Keywords:  Acute inflammation; Deacetylation; HDAC10; NLRP3 inflammasome; Ubiquitination

DOI:  https://doi.org/10.1186/s12964-024-01992-1
Front Microbiol. 2024 ;15 1503184

Characterization of acidic lysine acylations in mycobacteria.

Tong Ye, Danfeng Wang, Yewen Sun, Shuyu Xie, Tianqi Liu, Nana Tian, Minjia Tan, Jun-Yu Xu.

   Introduction: Protein acetylation is an extensively investigated post-translational modification (PTM). In addition to lysine acetylation, three new types of lysine acylations characterized by the presence of an acidic carboxylic group have been recently identified and validated. These included lysine malonylation (Kmal), lysine succinylation (Ksucc) and lysine glutarylation (Kglu). Pathogens belonging to the genus Mycobacterium elicit severe diseases in mammalian hosts through the modulation of energy metabolism pathways. Throughout this process, malonyl-CoA, succinyl-CoA and glutaryl-CoA are important intermediates in metabolic pathways, including the tricarboxylic acid (TCA) cycle, amino acid and lipid metabolism. These short-chain acyl-CoAs serve as substrates for corresponding acidic lysine acylation reactions. However, the landscape of these acyl-CoAs dependent acidic lysine acylomes remains unclear.
Methods: We used the high-affinity antibody enrichment combined with high-resolution LC-MS/MS analysis to systematically investigate the global proteomic characteristics of the three acidic lysine acylations in Mycobacterium smegmatis. Subsequently, we employed in vitro enzymatic assays to validate the functional impact of acylated substrates, adenylate kinase and proteasome-associated ATPase. Furthermore, we investigated the effects of overexpressing these two substrates on the in vitro growth of Mycobacterium smegmatis, its invasion of THP-1 cells, and the influence on inflammatory cytokines.
Results: We systematically investigated the global substrate characterization of 1,703 lysine malonylated sites, 5,320 lysine succinylated sites and 269 lysine glutarylated sites in the non-pathogenic model strain Mycobacterium smegmatis. Bioinformatics analysis demonstrated a correlation between these acidic lysine acylations and the functional roles of ribosomes, in addition to their roles in various metabolic pathways. Furthermore, we investigated the impact of lysine acylations on the functional activity of adenylate kinase and proteasome-associated ATPase, as well as their roles in mycobacterial infection process.
Discussion: Collectively, our study provided an important resource on substrate characterization and functional regulation of acidic lysine acylations in Mycobacterium smegmatis, giving valuable insights into their interrelation with the biology of infectious process.

Keywords:  Mycobacterium smegmatis; acidic lysine acylation; functional regulation; lysine glutarylation; lysine malonylation; lysine succinylation

DOI:  https://doi.org/10.3389/fmicb.2024.1503184
J Biol Chem. 2024 Dec 18. pii: S0021-9258(24)02597-3. [Epub ahead of print] 108095

Inositol phosphates dynamically enhance stability, solubility and catalytic activity of mTOR.

Lucia E Rameh, John D York, Raymond D Blind.

  Mechanistic Target of Rapamycin (mTOR) binds the small metabolite inositol hexakisphosphate (IP6) as shown in structures of mTOR, however it remains unclear if IP6, or any other inositol phosphate species, function as an integral structural element(s) or catalytic regulator(s) of mTOR. Here, we show that multiple, exogenously added inositol phosphate species can enhance the ability of mTOR and mTORC1 to phosphorylate itself and peptide substrates in in vitro kinase reactions, with the higher order phosphorylated species being more potent (IP6=IP5>IP4>>IP3). IP6 increased the VMAX and decreased the apparent KM of mTOR for ATP. Although IP6 did not affect the apparent KM of mTORC1 for ATP, monitoring kinase activity over longer reaction times showed increased product formation, suggesting inositol phosphates stabilize an active form of mTORC1 in vitro. The effects of IP6 on mTOR were reversible, suggesting IP6 bound to mTOR can be exchanged dynamically with the free solvent. Interestingly, we also observed that IP6 could alter mTOR electrophoretic mobility under denaturing conditions and its solubility in the presence of manganese. Together, these data suggest for the first time that multiple inositol phosphate species (IP6, IP5, IP4 and to a lesser extent IP3) can dynamically regulate mTOR and mTORC1 by promoting a stable, more soluble active-state of the kinase. Our data suggest that studies of the dynamics of inositol phosphate regulation of mTOR in cells are well justified.

Keywords:  enzyme kinetics; inositol hexakisphosphate; inositol phosphates; kinase; kinetics; mTOR; mTOR complex; signaling

DOI:  https://doi.org/10.1016/j.jbc.2024.108095
Elife. 2024 Dec 27. pii: RP97228. [Epub ahead of print]13

N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine.

Chuchu Wang, Chunyu Zhao, Hu Xiao, Jiali Qiang, Zhenying Liu, Jinge Gu, Shengnan Zhang, Dan Li, Yaoyang Zhang, Jacqueline Burré, Jiajia Diao, Cong Liu.

  Previously, we reported that α-synuclein (α-syn) clusters synaptic vesicles (SV) Diao et al., 2013, and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering Lai et al., 2023. Meanwhile, post-translational modifications (PTMs) of α-syn such as acetylation and phosphorylation play important yet distinct roles in regulating α-syn conformation, membrane binding, and amyloid aggregation. However, how PTMs regulate α-syn function in presynaptic terminals remains unclear. Here, based on our previous findings, we further demonstrate that N-terminal acetylation, which occurs under physiological conditions and is irreversible in mammalian cells, significantly enhances the functional activity of α-syn in clustering SVs. Mechanistic studies reveal that this enhancement is caused by the N-acetylation-promoted insertion of α-syn's N-terminus and increased intermolecular interactions on the LPC-containing membrane. N-acetylation in our work is shown to fine-tune the interaction between α-syn and LPC, mediating α-syn's role in synaptic vesicle clustering.

Keywords:  alpha-synuclein; lysophosphatidylcholine; membrane binding; molecular biophysics; mouse; structural biology; synaptic vesicle

DOI:  https://doi.org/10.7554/eLife.97228
Acta Biochim Biophys Sin (Shanghai). 2024 Dec 24.

Structure-based design of covalent nanobody binders for a thermostable green fluorescence protein.

Zhihao Yue, Yanfang Li, Hongmin Cai, Hebang Yao, Dianfan Li, Aimin Ni, Tingting Li.

  The use of green fluorescence protein (GFP) has advanced numerous areas of life sciences. An ultra-thermostable GFP (TGP), engineered from a coral GFP, offers potential advantages over traditional jellyfish-derived GFP because of its high stability. However, owing to its later discovery, TGP lacks the extensive toolsets available for GFP, such as heavy chain-only antibody binders known as nanobodies. In this study, we report the crystal structure of TGP in complex with Sb92, a synthetic nanobody identified from a previous in vitro screening, revealing Sb92's precise three-dimensional epitope. This structural insight, alongside the previously characterized Sb44-TGP complex, allows us to rationally design disulfide bonds between the antigen and the antibody for tighter interactions. Using biochemical analysis, we identify two bridged complexes (TGP A18C-Sb44 V100C and TGP E118C-Sb92 S57C), with the TGP-Sb92 disulfide pair showing high resistance to reducing agents. Our study expands the toolkit available for TGP and should encourage its wider applications.

Keywords:  disulfide engineering; rational design; synthetic nanobody; thermostable green fluorescence protein

DOI:  https://doi.org/10.3724/abbs.2024233
Philos Trans A Math Phys Eng Sci. 2024 Dec 30. 382(2287): 20230332

Limitations in quantum metrology approaches to imaging resolution.

S Iqbal, Y Xu, R W Boyd.

  Can a quantum advantage for imaging resolution be realized with the help of quantum estimation theory? We expect so, but we show that, presently, theoretical tools are insufficiently developed to answer this question for extended objects. Still, there is much to be learned from the current state of the art. In this review, we re-examine prominent results in the literature and probe the limits of quantum metrology in addressing imaging resolution. In particular, we show that under restrictive but well-defined conditions, any quantum advantage in one-dimensional phase imaging appears to diminish for increasingly detailed objects. We also show that a previous attempt at tackling this question, while incomplete, does predict an advantage for single-molecule localization microscopy, although this method may not be feasible in the near term. As for experimental claims of Heisenberg-limited imaging resolution, we briefly address the many inherent difficulties in demonstrating that such a thing has indeed been achieved.This article is part of the theme issue 'The quantum theory of light'.

Keywords:  localization; quantum imaging; quantum metrology; quantum optics; super-resolution

DOI:  https://doi.org/10.1098/rsta.2023.0332
Biochem Biophys Res Commun. 2024 Dec 18. pii: S0006-291X(24)01737-6. [Epub ahead of print]744 151201

Structural and biochemical characterization of a zinc metallopeptidase from Porphyromonas gingivalis.

Chunyang Feng, Weili Yu, Yongliang Jiang, Rong Xia.

  The pathogen Porphyromonas gingivalis contributes to the pathogenesis of periodontitis and other systemic diseases. The zinc-dependent metallopeptidase PepO is a virulence factor that plays a crucial role in the adhesion and invasion of Porphyromonas gingivalis to human cells. Here, we solved the 2.04 Å crystal structure of wild-type PepO in complex with the inhibitor phosphoramidon. The active-site pocket of PepO appears to exhibit an increased hydrophobicity and a more pronounced negative charge, highlighting distinct structural features compared to its homologs. In addition to phosphoramidon, several zinc metallopeptidase inhibitors, including thiorphan, omapatrilat, and sacubitrilat, exhibited varying degrees of inhibition on PepO enzymatic activity. Notably, the recombinant PepO showed distinct binding profiles to human fibrinogen, a characteristic that likely contributes to its role as virulence factors. These findings provide significant insights into the structural and functional mechanisms of PepO, offering a platform for the rational design of targeted inhibitors against the periodontal pathogen P. gingivalis.

Keywords:  Crystallography; Fibrinogen; Inhibitor; PepO; Protein structure; Zinc metallopeptidase

DOI:  https://doi.org/10.1016/j.bbrc.2024.151201
bioRxiv. 2024 Dec 10. pii: 2024.12.06.626451. [Epub ahead of print]

Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

Pornlada Likasitwatanakul, Zhixin Li, Paul Doan, Sandor Spisak, Akhouri Kishore Raghawan, Qi Liu, Priscilla Liow, Sunwoo Lee, David Chen, Pratyusha Bala, Pranshu Sahgal, Daulet Aitymbayev, Jennifer S Thalappillil, Malvina Papanastasiou, William Hawkins, Steven A Carr, Haeseong Park, James M Cleary, Jun Qi, Nilay S Sethi.

Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.
BRIEF SUMMARY: HDAC1/2 inhibition promotes colorectal cancer differentiation via gains in H3K27ac, which can be reversed by blocking its acetyltransferase EP300.

DOI: https://doi.org/10.1101/2024.12.06.626451
FEBS Open Bio. 2024 Dec 23.

Cost-effective and simple flow cytometry quantification of receptor-mediated autophagy using fluorescent tagging.

Mija Marinković, Ana Rožić, Denis Polančec, Ivana Novak.

  Mitophagy, a selective clearance of damaged or superfluous mitochondria via autophagy machinery and lysosomal degradation, is an evolutionarily conserved process essential for various physiological functions, including cellular differentiation and immune responses. Defects in mitophagy are implicated in numerous human diseases, such as neurodegenerative disorders, cancer, and metabolic conditions. Despite significant advancements in mitophagy research over recent decades, novel and robust methodologies are necessary to elucidate its molecular mechanisms comprehensively. In this study, we present a detailed protocol for quantitatively assessing mitophagy through flow cytometry using a mitochondria-targeted fluorescent mitophagy receptor, GFP-BNIP3L/NIX. This method offers a rapid alternative to conventional microscopy or immunoblotting techniques for analyzing mitophagy activity. Additionally, this approach can theoretically be adapted to utilize any fluorescent-tagged selective autophagy receptor, enabling the direct and rapid analysis of various types of receptor-mediated selective autophagy.

Keywords:  BNIP3L/NIX; flow cytometry; fluorescent tagging; receptor‐mediated mitophagy

DOI:  https://doi.org/10.1002/2211-5463.13958
Biol Cell. 2024 Dec 20. e2400096

Phosphoinositide signaling in the nucleus: Impacts on chromatin and transcription regulation.

Nesrine Hifdi, Mathilde Vaucourt, Karim Hnia, Ganna Panasyuk, Marie Vandromme.

Phosphoinositides also called Polyphosphoinositides (PPIns) are small lipid messengers with established key roles in organelle trafficking and cell signaling in response to physiological and environmental inputs. Besides their well-described functions in the cytoplasm, accumulating evidences pointed to PPIns involvement in transcription and chromatin regulation. Through the description of previous and recent advances of PPIns implication in transcription, this review highlights key discoveries on how PPIns modulate nuclear factors activity and might impact chromatin to modify gene expression. Finally, we discuss how PPIns nuclear and cytosolic metabolisms work jointly in orchestrating key transduction cascades that end in the nucleus to modulate gene expression.

DOI: https://doi.org/10.1111/boc.202400096
Int J Biol Macromol. 2024 Dec 20. pii: S0141-8130(24)09868-4. [Epub ahead of print] 139057

Regulation of autophagy and cellular signaling through non-histone protein methylation.

Yongfen Bao, Yaoyao Ma, Wentao Huang, Yujie Bai, Siying Gao, Luyao Xiu, Yuyang Xie, Xinrong Wan, Shigang Shan, Chao Chen, Lihua Qu.

  Autophagy is a highly conserved catabolic pathway that is precisely regulated and plays a significant role in maintaining cellular metabolic balance and intracellular homeostasis. Abnormal autophagy is directly linked to the development of various diseases, particularly immune disorders, neurodegenerative conditions, and tumors. The precise regulation of proteins is crucial for proper cellular function, and post-translational modifications (PTMs) are key epigenetic mechanisms in the regulation of numerous biological processes. Multiple proteins undergo PTMs that influence autophagy regulation. Methylation modifications on non-histone lysine and arginine residues have been identified as common PTMs critical to various life processes. This paper focused on the regulatory effects of non-histone methylation modifications on autophagy, summarizing related research on signaling pathways involved in autophagy-related non-histone methylation, and discussing current challenges and clinical significance. Our review concludes that non-histone methylation plays a pivotal role in the regulation of autophagy and its associated signaling pathways. Targeting non-histone methylation offers a promising strategy for therapeutic interventions in diseases related to autophagy dysfunction, such as cancer and neurodegenerative disorders. These findings provide a theoretical basis for the development of non-histone-methylation-targeted drugs for clinical use.

Keywords:  Arginine methylation; Autophagy; Lysine methylation; Non-histone; Post-translational modification; Signaling pathway

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.139057