bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2026–01–04
eighteen papers selected by
Lakesh Kumar, BITS Pilani
  1. From nucleation to capping: The lifecycle of an actin filament in Toxoplasma gondii gliding.
  2. The cell cycle-regulated cytoplasmic kinase, TgCRCK1, is required for efficient propagation of human protozoan pathogen, Toxoplasma gondii.
  3. Thrill seekers: how parasites change host behaviour.
  4. Toxoplasma gondii-induced ferroptosis contributes to acute lung injury in mice.
  5. A novel anti-Toxoplasma peptide suppresses parasite invasion and rescues host autophagic defenses.
  6. High-resolution cryo-EM meets parasitology in structural models of the conoid from Toxoplasma.
  7. Nonhistone deacetylation: a switch for crop resilience.
  8. SIRT6 in Cancer: Mechanistic Insights into Its Dual Roles in Cancer Biology and Implications for Precision Therapeutic Development.
  9. The BRD4-nucleosome interaction is enhanced modestly and non-selectively by histone acetylation.
  10. FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
  11. Thermal shift engagement assay for Class IIA histone deacetylase inhibitor screening.
  12. Phenylalanine Ammonia-Lyase: A Core Regulator of Plant Carbon Metabolic Flux Redistribution-From Molecular Mechanisms and Growth Modulation to Stress Adaptability.
  13. Legionella effector Ceg10 acetylates RPS20 to inhibit host translation and induce cell cycle arrest.
  14. The metabolic-epigenetic interface: lysine succinylation orchestrates bidirectional crosstalk in neurodegenerative disorders.
  15. Simultaneous single-cell proteomics and epigenetic analysis of histone deacetylase inhibition in human cells.
  16. Evaluation of Metabolic Characteristics of Cancer Cells.
  17. PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates.
  18. SigmaR1 is an auxiliary translocon factor with lipid-binding activity that regulates protein and lipid droplet homeostasis.
  1. Vet Parasitol. 2025 Dec 23. pii: S0304-4017(25)00290-0. [Epub ahead of print]342 110679
    From nucleation to capping: The lifecycle of an actin filament in Toxoplasma gondii gliding.
    Muhammad Farhab, Yu-Guo Yuan.
      Toxoplasma gondii is an obligate intracellular apicomplexan parasite whose motility, host cell invasion, and egress are powered by a unique actomyosin system. Unlike canonical actins that form stable filaments, T. gondii actin (TgACT1) is highly dynamic, existing predominantly in a monomeric state. This review traces the lifecycle of TgACT1, from nucleation to capping, to elucidate how the parasite harnesses rapid cytoskeletal turnover for gliding motility. This review discusses how TgACT1's intrinsic properties-including isodesmic polymerization, rapid subunit turnover, and specific amino acid substitutions that confer instability-are complemented by a minimal set of TgACT1-binding proteins (e.g., formins, TgPRF, toxofilin, ADF) to maintain a readily available pool of polymerization-competent monomers. The force for motility is generated by the glideosome, a specialized motor complex where myosin A walks along short, dynamic filaments, translocating adhesins rearward to propel the parasite. Finally, the therapeutic potential of targeting this essential and divergent system is discussed, highlighting the druggability of TgACT1 and the immunogenic properties of key regulators. Understanding the molecular mechanisms of TgACT1 dynamics reveals vulnerabilities that could be exploited for novel anti-parasitic strategies.
    Keywords:  Drug target; Gliding motility; T. gondii; TgACT1; TgACT1-Binding proteins; Vaccine
    DOI:  https://doi.org/10.1016/j.vetpar.2025.110679
  2. Microbiol Spectr. 2025 Dec 31. e0269125
    The cell cycle-regulated cytoplasmic kinase, TgCRCK1, is required for efficient propagation of human protozoan pathogen, Toxoplasma gondii.
    Dima Hajj Ali, Ramu Anandakrishnan, Frank O Aylward, Rajshekhar Y Gaji.
      Toxoplasma gondii is an obligate intracellular parasite that relies on a complex network of protein kinases to regulate essential processes such as invasion, replication, and egress. The Toxoplasma genome encodes approximately 159 kinases, yet only a small subset has been characterized. Our group is interested in defining the role of cell cycle-regulated kinases important for Toxoplasma fitness. In this study, we investigated the role of an uncharacterized, cell cycle-regulated cytoplasmic kinase, which we named TgCRCK1, in parasite biology and pathogenesis. Using endogenous tagging and immunofluorescence assays, we demonstrated that TgCRCK1 is a cytosolic kinase exhibiting a cell cycle-dependent expression pattern. Conditional depletion of TgCRCK1 via an auxin-inducible degron system impaired parasite growth, primarily due to defects in cell division and invasion. Transcriptomic analysis of TgCRCK1-deficient parasites revealed 93 differentially expressed genes, many involved in metabolism, gene expression, and intracellular transport. Although TgCRCK1 is essential for parasite growth, its depletion did not reduce Toxoplasma virulence in the mouse model. Collectively, these findings identify TgCRCK1 as a key factor contributing to Toxoplasma propagation.IMPORTANCEToxoplasma gondii is the primary causative agent of toxoplasmosis, infecting a broad range of warm-blooded animals, including humans. The parasite depends on a complex network of protein kinases for growth and pathogenesis, yet the functions of many remain uncharacterized. In this study, we present the initial characterization of TgCRCK1, a cytoplasmic kinase with temporally regulated expression. Our results demonstrate that loss of TgCRCK1 impairs parasite growth in vitro by disrupting parasite division and host-cell invasion. However, studies in an animal model indicate that TgCRCK1 is not essential for acute toxoplasmosis. Together, these findings provide foundational insights into the localization, expression, and function of TgCRCK1 in this important human pathogen.
    Keywords:  Toxoplasma gondii; auxin-inducible degron system; cell cycle regulation; lytic cycle; protein kinases
    DOI:  https://doi.org/10.1128/spectrum.02691-25
  3. Vet Rec. 2026 Jan 03. 198(1): 10-11
    Thrill seekers: how parasites change host behaviour.
    Josh Loeb.
      Josh Loeb reports on a new study that found that rats infected with Toxoplasma gondii are less risk averse, making them more likely to fall prey to cats.
    DOI:  https://doi.org/10.1002/vetr.70272
  4. Parasit Vectors. 2025 Dec 28.
    Toxoplasma gondii-induced ferroptosis contributes to acute lung injury in mice.
    Xiaodan Yuan, Zhenzhen Liu, Yeting Ma, Feixue Liu, Penglin Bao, Boya Du, Xu Zhang, Pengtao Gong, Nan Zhang, Jianhua Li, Xin Li, Xiaocen Wang.
       BACKGROUND: Toxoplasma gondii (T. gondii) is an important apicomplexan parasite that causes zoonotic toxoplasmosis in humans and animals. Acute T. gondii infection leads to systemic immunopathology that may manifest as lung injury or pulmonary embolism. Ferroptosis is an iron-dependent regulated cell death driven by lethal lipid hydroperoxide accumulation. Emerging evidence implicates ferroptosis in infection-related tissue damage; however, the role of ferroptosis in T. gondii-induced lung injury remains to be explored.
    METHODS: Mice were infected with T. gondii to establish a lung injury model. The body weight changes, survival rate, inflammatory cytokines, lung histopathology, and parasite burden were assessed. The key ferroptosis-related indicators involved in antioxidant, iron metabolism, and lipid metabolism pathways were analyzed in lung tissues using techniques such as transmission electron microscopy, western blotting, and immunohistochemistry. Deferiprone (DFP), an oral iron chelator that can inhibit ferroptosis, was used to investigate the potential role of ferroptosis in T. gondii lung injury.
    RESULTS: T. gondii infection induced lung injury in mice with thickening of alveolar septa and hemorrhage in alveolar spaces, accompanied by iron deposition. Crucially, T. gondii triggered ferroptosis in lung tissues of mice, evidenced by MDA elevation, GSH depletion, total iron and Fe2+ overload, and mitochondrial cristae loss. Furthermore, iron metabolism pathways were disordered while antioxidant pathways were suppressed. DFP treatment reversed ferroptosis alterations, decreased inflammatory cytokines, attenuated pathological changes, reduced T. gondii burden, and prolonged survival of the infected mice.
    CONCLUSIONS: Our findings revealed that T. gondii infection triggered ferroptosis by compromising dysregulated iron metabolism and antioxidant defenses, playing a key role in T. gondii-induced lung injury. DFP exhibited a promising therapy effect for toxoplasmosis.
    Keywords:   Toxoplasma gondii ; Antioxidant; Deferiprone; Ferroptosis; Iron; Lung injury
    DOI:  https://doi.org/10.1186/s13071-025-07207-x
  5. Microbiol Spectr. 2025 Dec 29. e0221825
    A novel anti-Toxoplasma peptide suppresses parasite invasion and rescues host autophagic defenses.
    Ji Zhao, Baocan Zhuang, Yun Yang, Elvis Quansah, Yuanyuan Cao, Qingli Luo, Jilong Shen, Li Yu.
      Toxoplasma gondii, a ubiquitous intracellular protozoan parasite, poses life-threatening risks to immunocompromised hosts. Current first-line treatments for toxoplasmosis are limited by significant toxicity and high post-treatment recurrence rates. In this study, we employed phage display technology to identify peptides targeting TgMIC6 and disrupting its immune evasion function. Among these, the C8 peptide exhibited dual efficacy: it not only inhibited T. gondii invasion in vitro but also restored host autophagy, countering the parasite's immune escape mechanisms. Furthermore, in vivo studies confirmed the potent parasiticidal activity of C8 against multiple T. gondii strains. These findings highlight C8 as a promising therapeutic candidate for toxoplasmosis.IMPORTANCEThe study identifies the C8 peptide as a novel anti-Toxoplasma agent with dual efficacy: it directly inhibits parasite invasion and restores host autophagy compromised by T. gondii immune evasion. Demonstrating potent parasiticidal activity in vitro and in vivo, C8 significantly prolongs survival in acute infection models across multiple strains without cytotoxicity. Its multi-target mechanism and favorable safety profile address critical limitations of current therapies. While stability and chronic infection efficacy require optimization, C8 represents a promising peptide-based therapeutic candidate, offering a foundation for developing next-generation anti-toxoplasmosis drugs with enhanced specificity and reduced side effects. This work highlights the potential of peptide biologics in combating apicomplexan infections.
    Keywords:  TgMIC6; Toxoplasma gondii; autophagy; peptide
    DOI:  https://doi.org/10.1128/spectrum.02218-25
  6. Nat Struct Mol Biol. 2026 Jan 02.
    High-resolution cryo-EM meets parasitology in structural models of the conoid from Toxoplasma.
      
    DOI:  https://doi.org/10.1038/s41594-025-01729-9
  7. Trends Plant Sci. 2025 Dec 26. pii: S1360-1385(25)00361-9. [Epub ahead of print]
    Nonhistone deacetylation: a switch for crop resilience.
    Minghui Xing, Lam-Son Phan Tran, Weiqiang Li, Xiaojian Yin.
      HISTONE DEACETYLASE (HDAC)-mediated nonhistone deacetylation is an evolutionarily conserved post-translational modification (PTM) essential for plant stress adaptation. Recently, two HDAC modules involved in plant responses to drought and pathogens, respectively, were functionally analyzed by Liu et al. and Zhang et al., providing evidence that biotic and abiotic stress-triggered relief of deacetylation functions as a switch for crop resilience.
    Keywords:  Crop stress resilience; HDAC-mediated non-histone deacetylation; stress signaling; wheat
    DOI:  https://doi.org/10.1016/j.tplants.2025.12.007
  8. Biomolecules. 2025 Nov 26. pii: 1655. [Epub ahead of print]15(12):
    SIRT6 in Cancer: Mechanistic Insights into Its Dual Roles in Cancer Biology and Implications for Precision Therapeutic Development.
    Yanqi Feng, Zhuoyan Han, Kunrui Zhu, Yuelin Han, Xiangtian Xiao, Jie Tong, Yiming Li, Shu Xia.
      Sirtuin 6 (SIRT6), a (Nicotinamide adenine dinucleotide) NAD+-dependent deacylase and mono- (adenosine diphosphate) ADP-ribosyltransferase, is increasingly recognized as a pivotal regulator of genomic stability, metabolic reprogramming, and epigenetic remodeling. This review synthesizes current evidence on the dual roles of SIRT6 in cancer, highlighting its context-dependent functions as both a tumor suppressor and promoter across various malignancies. We detail its involvement in DNA damage sensing, repair coordination, glycolytic regulation, and chromatin modification, and discuss how these mechanisms contribute to tumor initiation, progression, and therapy resistance. Emerging therapeutic strategies targeting SIRT6, including small-molecule modulators, genetic interventions, and combination therapies, are critically evaluated. Our analysis underscores the necessity for context-specific therapeutic targeting, and pharmacological modulation of SIRT6 represents a promising avenue for precision oncology.
    Keywords:  SIRT6; context-dependent duality; metabolic reprogramming; precision oncology
    DOI:  https://doi.org/10.3390/biom15121655
  9. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1406. [Epub ahead of print]53(22):
    The BRD4-nucleosome interaction is enhanced modestly and non-selectively by histone acetylation.
    Lucien S Lambrechts, Xavier J Reid, Lucas Kambanis, Clement Luong, Erekle Kobakhidze, Andrea Daners, Yichen Zhong, Karishma Patel, Charlotte K Franck, Hakimeh Moghaddas Sani, Cameron Taylor, Jason K K Low, Richard J Payne, Joel P Mackay.
      BRD4 regulates gene transcription in complex eukaryotes, in part through the binding of its tandem bromodomains to acetylated lysine residues found in histones and transcription factors. Despite pharmacological inhibition of these domains showing promise in preclinical studies, clinical trial data have been less encouraging so far. A stronger understanding of BRD4 biochemistry could provide a route to better outcomes. To advance on prior work, which has focused almost entirely on the binding of isolated bromodomains and acetylated peptides, we have sought the preferred nucleosomal binding partner of full-length BRD4. We demonstrate that BRD4 binds with sub-micromolar affinity to both unmodified nucleosomes and to DNA alone. In strong contrast to BRD4-peptide interactions, we also find that the affinity of BRD4 for nucleosomes is increased only 2-4-fold by histone acetylation and that this affinity has little dependence on the acetylation pattern. Despite this modest effect of acetylation, binding of BRD4 to acetyllysine in the nucleosome was more resistant to perturbation by mutation or small-molecule inhibition than BRD4-peptide interactions. Our work on a more complete in vitro system helps bridge the gap between cellular and prior in vitro work and provides clues to explain the in vivo chromatin occupancy profile of BRD4 and how it changes upon therapeutic inhibition.
    DOI:  https://doi.org/10.1093/nar/gkaf1406
  10. Sci Adv. 2026 Jan 02. 12(1): eaea8771
    FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
    Masayoshi Higuchi, August F Williams, Anna E Stuhlfire, Ariel H Nguyen, David A G Gervasio, Claire E Turkal, Suejean Chon, Matthew J Hangauer.
      Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis, but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione, and various ferroptosis-suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is down-regulated in multiple persister cell types, and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely on residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition down-regulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induces reactive oxygen species and sensitizes multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.
    DOI:  https://doi.org/10.1126/sciadv.aea8771
  11. Results Chem. 2025 Nov;pii: 102682. [Epub ahead of print]18
    Thermal shift engagement assay for Class IIA histone deacetylase inhibitor screening.
    Lauren N Kotsull, Mary Kay H Pflum.
      Histone deacetylase (HDAC) proteins are the targets of several anti-cancer clinical drugs, which motivates future inhibitor development. Class IIA HDAC proteins, HDAC4, HDAC5, HDAC7, and HDAC9, are pseudodeacetylases that lack a key catalytic amino acid residue resulting in low deacetylase activity. Yet enzymatic deacetylase activity assays are typically used to assess inhibitor potency. A ligand binding assay is needed for a more relevant assessment of inhibitor engagement by class IIA HDAC proteins. As an efficient method to directly assess inhibitor binding, thermal shift assays were developed for HDAC4, 5, and 7. Consistent with prior activity assays, thermal shift analysis reproduced the expected binding of various inhibitors to HDAC1, HDAC4, HDAC5, and HDAC7. Additionally, a higher throughput thermal shift format was developed using dot blot analysis. Thermal shift analysis offers a useful complement to enzyme activity assays for characterization of HDAC inhibitors.
    Keywords:  Dot blot; HDAC; HDAC inhibitor; Histone deacetylase; Thermal shift
    DOI:  https://doi.org/10.1016/j.rechem.2025.102682
  12. Plants (Basel). 2025 Dec 14. pii: 3811. [Epub ahead of print]14(24):
    Phenylalanine Ammonia-Lyase: A Core Regulator of Plant Carbon Metabolic Flux Redistribution-From Molecular Mechanisms and Growth Modulation to Stress Adaptability.
    Xiaozhu Wu, Suqing Zhu, Lisi He, Gongmin Cheng, Tongjian Li, Wenying Meng, Feng Wen.
      Phenylalanine ammonia-lyase (PAL) is the core branch-point enzyme connecting plant primary aromatic amino acid metabolism to the phenylpropanoid pathway, which determines carbon flux redistribution between growth and defense and is essential for plant adaptation to various environments. Extensive research has clarified PAL's conserved homotetrameric structure, MIO cofactor-dependent catalytic mechanism, and its roles in plant growth, development, and stress responses. However, there is a lack of comprehensive review studies focusing on PAL-mediated carbon metabolic flux redistribution, specifically covering its structural and evolutionary foundations, the links between this flux regulation and plant growth/development, its multi-layered regulatory network, and its roles in stress adaptation, limiting a comprehensive understanding of its evolutionary and functional diversity. This review systematically covers four core aspects: first, the molecular foundation, encompassing PAL's structural features and catalytic specificity governed by the MIO cofactor; second, evolutionary diversity spanning from algae to angiosperms, with emphasis on unique regulatory mechanisms and evolutionary significance across lineages; third, the multi-layered regulatory network, integrating transcriptional control, post-translational modifications, epigenetic regulation, and functional crosstalk with phytohormones; and fourth, functional dynamics, which elaborate PAL's roles in organ development, including root lignification, stem mechanical strength, leaf photoprotection, flower and fruit quality formation, and lifecycle-wide dynamic expression, as well as its mediated stress adaptations and regulatory networks under combined stresses. These insights provide a theoretical basis for targeted manipulation of PAL to optimize crop carbon allocation, thus improving growth performance, enhance stress resilience, and promote sustainable agriculture.
    Keywords:  abiotic stresses; biotic challenges; carbon flux reallocation; growth and development; phenylalanine ammonia-lyase
    DOI:  https://doi.org/10.3390/plants14243811
  13. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2517995123
    Legionella effector Ceg10 acetylates RPS20 to inhibit host translation and induce cell cycle arrest.
    Jiajia Gao, Wenwen Xu, Ziyi Zhou, Lixin Lu, Zhenhuang Ge, Weiqiang Wang, Yongjun Lu, Honghua Ge.
      Legionella pneumophila, the causative agent of Legionnaires' disease, utilizes a type IV secretion system (T4SS) to translocate effectors into host cells, modulating diverse cellular processes to create a replication-permissive niche. Here, we characterize Ceg10, a T4SS-translocated effector, as a nucleus-targeting acetyltransferase that interferes with host ribosome biogenesis and cell cycle progression. Structural analysis reveals that Ceg10 harbors a conserved Cys-His-Asp (CHD) catalytic triad required for its acetyltransferase activity. Upon nuclear import mediated by the host transport adaptor HEATR3, Ceg10 selectively acetylates the ribosomal protein RPS20 at Thr64, Thr65, and Arg66, which have not been annotated as posttranslational modification sites. This acetylation impairs RPS20's interaction with RPS29 and 18S rRNA, two components critical for 40S ribosomal subunit assembly, leading to translation inhibition and G1/S cell cycle arrest. These host perturbations are essential for efficient early-stage intracellular replication of L. pneumophila. Our findings identify a distinct mechanism by which a bacterial effector co-opts nuclear import machinery and directly modifies ribosomal proteins to subvert host biosynthesis and cell cycle control, highlighting ribosomal protein acetylation as a hitherto unrecognized role in host-pathogen interactions.
    Keywords:  Legionella pneumophila; cell cycle arrest; protein acetylation; ribosomal protein RPS20; type IV secretion system
    DOI:  https://doi.org/10.1073/pnas.2517995123
  14. Front Neurol. 2025 ;16 1678595
    The metabolic-epigenetic interface: lysine succinylation orchestrates bidirectional crosstalk in neurodegenerative disorders.
    Fanglei Chai, Chong Liu, Yandong Liu, Wei Zou.
      Succinylation, a nexus between metabolism and epigenetic regulation, is a central factor in the onset and progression of neurodegenerative diseases (NDDs). Research has demonstrated a close association between NDDs and neuronal metabolic disorders. Succinylation regulates the interaction between energy metabolism and epigenetic networks, establishing the pathological mechanism of "metabolic-epigenetic bidirectional regulation." In metabolic stress, such as mitochondrial dysfunction or enhanced glycolysis, succinyl-CoA increases, causing uncontrolled succinylation. These modifications impair the function of proteins associated with synaptic plasticity, leading to disorders in synaptic transmission and neuronal damage. Concurrently, succinylation regulates the activity of enzymes involved in DNA methylation and epigenetic reprogramming, impairing neuronal recovery and creating a vicious cycle. This regulatory network displays bidirectional self-reinforcing characteristics. Metabolic disorders influence epigenetic states through succinylation. Epigenetic abnormalities inhibit the transcription of genes associated with mitochondrial metabolism, exacerbating energy metabolism defects and oxidative stress. This leads to irreversible degenerative changes in neurons. At the therapeutic level, targeting succinylation can disrupt the metabolic-epigenetic pathological loop and restore synaptic function. In short, understanding how succinylation is regulated may lead to new treatment options for neurodegenerative diseases.
    Keywords:  NDD; SIRT5; metabolic-epigenetic crosstalk; mitochondria; succinylation
    DOI:  https://doi.org/10.3389/fneur.2025.1678595
  15. Commun Biol. 2025 Dec 30.
    Simultaneous single-cell proteomics and epigenetic analysis of histone deacetylase inhibition in human cells.
    Benjamin C Orsburn.
      Single-cell proteomics by mass spectrometry (SCP) is an emerging technology in which hundreds or thousands of proteins can be directly quantified in typical human cells. As the proteins detected and quantified by SCP are heavily biased toward proteins of highest abundance, chromatin proteins are an attractive target for analysis. To this end, I applied SCP to the analysis of cancer cells treated with mocetinostat, a class specific histone deacetylase inhibitor. I find that 16 PTMs can be confidently identified and localized with high site specificity in single cells. Drug treatment reveals apparent heterogeneity in the abundance and distribution of the accumulated acetylation sites in histone tails. While other techniques exist to measure histone modifications in single human cells, the approach presented here allows simultaneous quantification of hundreds of proteins, allowing phenotypic insight as well as epigenetic inferences in each individual cell. All raw and processed data described in this study has been made publicly available through the ProteomeXchange/MASSIVE repository system as MSV000093434.
    DOI:  https://doi.org/10.1038/s42003-025-09452-3
  16. Methods Mol Biol. 2026 ;2983 159-167
    Evaluation of Metabolic Characteristics of Cancer Cells.
    Riddhi Mehta, Pritpal Kaur, Fatema Zohra Sadia, Patricia Maziarz, Ales Vancura.
      Cancer cells undergo a complex rearrangement of metabolic pathways that allows them to satisfy the needs of increased proliferation. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS) have emerged as a potential therapeutic strategy. In this chapter, we describe a protocol that utilizes the Agilent Seahorse XFp Analyzer to assess mitochondrial respiration and glycolysis in ovarian cancer cells.
    Keywords:  Cancer metabolism; Extracellular acidification; Glycolysis; Mitochondrial respiration; Ovarian cancer; Oxygen consumption rate
    DOI:  https://doi.org/10.1007/978-1-0716-4901-5_15
  17. Nat Chem Biol. 2025 Dec 29.
    PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates.
    Zhenguang Zhao, Wenqing Xu, Ethan Yang Feng, Shiyun Cao, Alba Hermoso-López, Pablo Peña-Vega, Hannah C Lloyd, Abigail K D Porter, Manuel Guzmán, Ning Zheng, Christina M Woo.
      The E3 ligase substrate adapter cereblon (CRBN), the primary target of clinical agents thalidomide and lenalidomide, recognizes endogenous substrates bearing the C-terminal cyclic imide modification. Although C-terminal cyclic imides can form spontaneously, an enzyme that regulates their formation and thereby promotes a biological pathway connecting substrates to CRBN is unknown. Here we report that protein carboxymethyltransferase (PCMT1) promotes formation of C-terminal cyclic imides on C-terminal asparagine residues of CRBN substrates. PCMT1 and CRBN coregulate the levels of metabolic enzymes including glutamine synthetase and inorganic pyrophosphatase 1 in vitro, in cells and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. The discovery of an enzyme that regulates CRBN substrates through the C-terminal cyclic imide reveals a previously unknown biological pathway that is perturbed by thalidomide derivatives and provides a biochemical basis for the connection between multiple biological processes and CRBN.
    DOI:  https://doi.org/10.1038/s41589-025-02106-9
  18. Nat Commun. 2025 Dec 31.
    SigmaR1 is an auxiliary translocon factor with lipid-binding activity that regulates protein and lipid droplet homeostasis.
    Xuewen Hu, Tiantian Zhou, Tiansi Cui, Yuanjiao Du, Chunyu Song, Weiping Chang, Juan Xiong, Jichao Qin, Lin Deng, Wei-Ke Ji.
      Sigma Non-Opioid Intracellular Receptor 1 (SigmaR1) is a member of the sigma family of receptors that interacts with a variety of psychotomimetic drugs and is involved in a wide range of cellular and physiological functions. Despite its increasing importance in human physiology and disease, the subcellular localization of SigmaR1 and its molecular function remain poorly defined. Using endogenous tagging and cell fractionation, we show that SigmaR1 is a type II integral ER membrane protein that is specifically enriched at ER sheets. A short region at the N-terminus of SigmaR1 promotes its ER-sheet localization. Importantly, our biochemical studies demonstrate that SigmaR1 directly interacts with components of the translocon complex including TRAPα and Nicalin. In addition, we found that a β-barrel at the C-terminal of SigmaR1 binds phosphatidylcholine (PC), and the binding of PC strengthens the association of SigmaR1 with the translocon complex. SigmaR1 knockout systematically impaired cellular protein and lipid homeostasis, resulting in accumulation of lipid droplets in hepatocytes. Collectively, we propose that SigmaR1 is an auxiliary translocon factor that binds lipids to regulate protein and lipid droplet homeostasis, which may underlie the broad and vital roles of SigmaR1 in physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-025-68157-7
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒27 at 5:18.