bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–03–09
nine papers selected by
Bruna Martins Garcia, CABIMER
  1. Insights into palmitoylation-mediated regulation of inflammasomes.
  2. Regulation of Synaptic NMDA Receptor Activity by Post-Translational Modifications.
  3. Role of lysine lactylation in neoplastic and inflammatory pulmonary diseases (Review).
  4. Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism.
  5. New Types of Post-Translational Modification of Proteins in Cardiovascular Diseases.
  6. Post-translational modifications in hepatocellular carcinoma: unlocking new frontiers in immunotherapy.
  7. The landscape of renal protein S-acylation in mice with lipid-induced nephrotoxicity.
  8. Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications.
  9. The multifaceted role of post-translational modifications of LSD1 in cellular processes and disease pathogenesis.
  1. Trends Immunol. 2025 Mar 05. pii: S1471-4906(25)00035-3. [Epub ahead of print]
    Insights into palmitoylation-mediated regulation of inflammasomes.
    Qiwei Jiang, Lang Bu, Jianping Guo.
      The mammalian inflammasome is crucial for responding to environmental/intrinsic stress, and its regulation remains a significant focus in immune-mediated inflammatory diseases and antitumor immunity. Recent studies highlight a close link between palmitoylation and inflammasome regulation. However, this type of regulation remains elusive but may harbor potential for combating inflammation-driven disorders.
    Keywords:  NLRP3; gasdermin D; inflammasome; mitochondrial antiviral signaling protein; palmitoylation
    DOI:  https://doi.org/10.1016/j.it.2025.02.008
  2. Neurochem Res. 2025 Mar 03. 50(2): 110
    Regulation of Synaptic NMDA Receptor Activity by Post-Translational Modifications.
    Emanuel Tahiri, Elisa Corti, Carlos B Duarte.
      NMDA receptors for the neurotransmitter glutamate are widely distributed in the central nervous system, playing important roles in brain development, function and plasticity. Alterations in their activity are also important mediators in neuropsychiatric and neurodegenerative disorders. The different NMDA receptor subunits (GluN1, GluN2A-D and GluN3A, B) share a similar structure and membrane topology, with an intracellular C-terminus tail responsible for the interaction with proteins important for the trafficking of the receptors, and to control their surface distribution and signalling activity. The latter sequence varies among subunits but consistently contains the majority of post-translational modification sites on NMDA receptors. These modifications, including phosphorylation, ubiquitination, and palmitoylation, regulate interactions with intracellular proteins. Differences in the amino acid sequence between NMDA receptor subunits lead to a differential regulation by post-translational modifications. Since NMDA receptors are formed by oligomerization of different subunits, and each subunit is regulated in a specific manner, this creates multiple possibilities for regulation of these receptors, with impact in synaptic function and plasticity. This review addresses the diversity of mechanisms involved in the post-translational modification of NMDA receptor subunits, and their impact on the activity and distribution of the receptors, as well as their function in nerve cells.
    Keywords:  Glutamatergic synapses; NMDA receptors; Palmitoylation; Phosphorylation; Synaptic plasticity; Ubiquitination
    DOI:  https://doi.org/10.1007/s11064-025-04346-6
  3. Int J Mol Med. 2025 May;pii: 71. [Epub ahead of print]55(5):
    Role of lysine lactylation in neoplastic and inflammatory pulmonary diseases (Review).
    Shanshan Wang, Hongyan Zheng, Jianping Zhao, Jungang Xie.
      Protein lysine lactylation is a ubiquitous and post‑translational modification of lysine residues that involves the addition of a lactyl group on both histone and non‑histone proteins. This process plays a pivotal role in human health and disease and was first discovered in 2019. This epigenetic modification regulates gene transcription from chromatin or directly influences non‑histone proteins by modulating protein‑DNA/protein interactions, activity and stability. The dual functions of lactylation in both histone and non‑histone proteins establish it as a crucial mechanism involved in various cellular processes, such as cell proliferation, differentiation, immune and inflammatory responses and metabolism. Specific enzymes, referred to as 'writers' and 'erasers', catalyze the addition or removal of lactyl groups at designated lysine sites, thereby dynamically modulating lactylation through alterations in their enzymatic activities. The respiratory system has a remarkably intricate metabolic profile. Numerous pulmonary diseases feature an atypical transition towards glycolytic metabolism, which is linked to an overproduction of lactate, a possible substrate for lactylation. However, there has yet to be a comprehensive review elucidating the full impact of lactylation on the onset, progression and potential treatment of neoplastic and inflammatory pulmonary diseases. In the present review, an extensive overview of the discovery of lactylation and advancements in research on the existing lactylation sites were discussed. Furthermore, the review particularly investigated the potential roles and mechanisms of histone and non‑histone lactylation in various neoplastic and inflammatory pulmonary diseases, including non‑small cell lung cancers, malignant pleural effusion, pulmonary fibrosis, acute lung injury and asthma, to excavate the new therapeutic effects of post‑translational modification on various pulmonary diseases.
    Keywords:  histone; lung cancer; lysine lactylation; pulmonary inflammatory diseases; writers and erasers
    DOI:  https://doi.org/10.3892/ijmm.2025.5512
  4. Cell Death Differ. 2025 Mar 05.
    Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism.
    Qijie Zhao, Shisheng Zhou, Wenhui Lou, Hui Qian, Zhiwei Xu.
      Cells produce metabolic intermediates through catalytic reactions, mainly via post-translational modifications. The modification of proteins by O-linked N-acetylglucosamine, known as O-GlcNAcylation, is one of the most common post-translational modifications. As O-GlcNAcylation and phosphorylation can occur at serine or threonine residues, it is crucial that the interplay between these two modifications is vital to bioenergetic and biosynthetic demand. Although emerging recognition linking O-GlcNAc modification and phosphorylation to protein functions has been obtained, the issue of how altered O-GlcNAcylation or phosphorylation regulates each other in the metabolic system remains uncertain. The combination of cell biological and proteomic approaches over the recent few years has not only highlighted the interactions between O-GlcNAcylation and phosphorylation in protein function but also prompted us to elucidate the underlying mechanisms behind this crosstalk controlling metabolic homeostasis. The purpose of this review is to summarize recent advances in the O-GlcNAcylation/phosphorylation regulation of the metabolic process. An extensive exploration of this interplay has significant implications for metabolic control systems, including glucose, lipid, and nucleotide metabolism, where dysregulation in O-GlcNAcylation and phosphorylation of metabolic syndrome is essential.
    DOI:  https://doi.org/10.1038/s41418-025-01473-z
  5. J Cardiovasc Transl Res. 2025 Mar 03.
    New Types of Post-Translational Modification of Proteins in Cardiovascular Diseases.
    Juntao Fang, Shaoyu Wu, Hengli Zhao, Chuanmeng Zhou, Ling Xue, Zhiyong Lei, Hui Li, Zhixin Shan.
      Post-translational modifications (PTMs), which are covalent alterations of proteins after their synthesis, are critical for their proper function and the maintenance of cellular physiology. The significance of PTMs in the context of cardiovascular diseases (CVDs) has been increasingly recognized due to their potential to influence protein stability, activity, and localization, thereby affecting the progression of CVDs. The identification and understanding of PTMs in CVDs at the molecular level are vital for the discovery of new biomarkers and new targets for clinical interventions. This article provides a comprehensive overview of the role and mechanisms of new types of PTMs, such as acetylation, crotonylation, succinylation, S-nitrosylation, malonylation, S-palmitonylation, β-hydroxybutyrylation and lactylation, in CVDs, highlighting their importance in advancing diagnostic and therapeutic approaches for CVDs.
    Keywords:  Cardiovascular diseases; Crotonylation; Lactylation; Post-translational modifications; Succinylation
    DOI:  https://doi.org/10.1007/s12265-025-10600-7
  6. Front Immunol. 2025 ;16 1554372
    Post-translational modifications in hepatocellular carcinoma: unlocking new frontiers in immunotherapy.
    Yuexian Piao, Naicui Zhai, Xiaoling Zhang, Wenjie Zhao, Min Li.
      Liver cancer, particularly hepatocellular carcinoma (HCC), is one of the most common and aggressive malignancies worldwide. Immunotherapy has shown promising results in treating HCC, but its efficacy is often limited by complex mechanisms of immune evasion. Post-translational modifications (PTMs) of proteins play a critical role in regulating the immune responses within the tumor microenvironment (TME). These modifications influence protein function, stability, and interactions, which either promote or inhibit immune cell activity in cancer. In this mini-review, we explore the diverse PTMs that impact immune evasion in liver cancer, including glycosylation, phosphorylation, acetylation, and ubiquitination. We focus on how these PTMs regulate key immune checkpoint molecules such as PD-L1, CTLA-4, and the TCR complex. Furthermore, we discuss the potential of targeting PTMs in combination with existing immunotherapies to enhance the effectiveness of treatment in HCC. Understanding the role of PTMs in immune regulation may lead to the development of novel therapeutic strategies to overcome resistance to immunotherapy in liver cancer.
    Keywords:  glycosylation; hepatocellular carcinoma; immunotherapy; lactylation; post-translation modification
    DOI:  https://doi.org/10.3389/fimmu.2025.1554372
  7. Sci Rep. 2025 Mar 05. 15(1): 7689
    The landscape of renal protein S-acylation in mice with lipid-induced nephrotoxicity.
    Fangrui Xiu, Zhibo Gai, Peter Gehrig, Witold E Wolski, Museer A Lone, Michele Visentin.
      Excess fat intake is associated with kidney toxicity and dysfunction. Because fatty acids can also be reversibly attached onto cysteine residues and modulate the function of several membrane-bound proteins, we studied the effect of high-fat diet (HFD) on the S-acylated proteome of mouse kidneys to uncover novel biochemical changes that might contribute to lipid-induced nephrotoxicity. We compared the S-acylated proteome of kidneys from mice fed a chow diet (CD) or a HFD. HFD caused albuminuria. The HFD intervention induced a large-scale repression of protein S-acylation as well as of the most abundant ceramides and sphingomyelin species, which are highly suggestive of a reduction in acyl-CoA availability. The HFD-induced S-acylation repression mostly affected proteins involved in endocytosis and intracellular transport. Notably, the kidneys of mice fed a HFD displayed a marked decrease in the total amount and in the S-acylated form of megalin, the main tubular protein retrieval system. Further in vitro experiments indicated that S-acylation inhibition results in a reduction of megalin protein level. We conclude that diet-induced derangement of fatty acid metabolism modifies the renal landscape of the S-acylated proteome during the early stages of the kidney injury, which might reduce the efficiency of protein reabsorption by the proximal tubule.
    Keywords:  Chronic kidney disease; High-fat diet; Proteinuria; Proteomics, S-acylation; S-palmitoylation
    DOI:  https://doi.org/10.1038/s41598-025-92530-7
  8. Mol Psychiatry. 2025 Mar 03.
    Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications.
    Liping Chen, Huihui Jiang, Julio Licinio, Haitao Wu.
      O-GlcNAcylation, a dynamic post-translational modification occurring on serine or threonine residues of numerous proteins, plays a pivotal role in various cellular processes, including gene regulation, metabolism, and stress response. Abundant in the brain, O-GlcNAcylation intricately governs neurodevelopment, synaptic assembly, and neuronal functions. Recent investigations have established a correlation between the dysregulation of brain O-GlcNAcylation and a broad spectrum of neurological disorders and injuries, spanning neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as injuries to the central nervous system (CNS). Manipulating O-GlcNAcylation has demonstrated neuroprotective properties against these afflictions. This review delineates the roles and mechanisms of O-GlcNAcylation in the CNS under both physiological and pathological circumstances, with a focus on its neuroprotective effects in neurological disorders and injuries. We discuss the involvement of O-GlcNAcylation in key processes such as neurogenesis, synaptic plasticity, and energy metabolism, as well as its implications in conditions like Alzheimer's disease, Parkinson's disease, and ischemic stroke. Additionally, we explore prospective therapeutic approaches for CNS disorders and injuries by targeting O-GlcNAcylation, highlighting recent clinical developments and future research directions. This comprehensive overview aims to provide insights into the potential of O-GlcNAcylation as a therapeutic target and guide future investigations in this promising field.
    DOI:  https://doi.org/10.1038/s41380-025-02943-z
  9. Genes Dis. 2025 May;12(3): 101307
    The multifaceted role of post-translational modifications of LSD1 in cellular processes and disease pathogenesis.
    Yinrui Li, Bo Wang, Yichao Zheng, Huiqin Kang, Ang He, Lijuan Zhao, Ningjie Guo, Hongmin Liu, Adil Mardinoglu, M A A Mamun, Ya Gao, Xiaobing Chen.
      Post-translational modifications (PTMs) of proteins play a crucial role in living organisms, altering the properties and functions of proteins. There are over 450 known PTMs involved in various life activities. LSD1 (lysine-specific demethylase 1) is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4 (H3K4) and histone H3 lysine K9 (H3K9). This ability of LSD1 allows it to inhibit or activate transcription. LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of these PTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders, neurological disorders, cardiovascular diseases, and bone diseases. Understanding the species of PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvement in diverse physiological and pathological processes. In this review, we discuss the structural characteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes. Furthermore, we describe human diseases associated with abnormal expression of LSD1. This comprehensive analysis sheds light on the intricate interplay between PTMs and the functions of LSD1, highlighting their significance in health and diseases.
    Keywords:  Enzyme activity; Histone demethylase; Human diseases; LSD1; Post-translational modifications
    DOI:  https://doi.org/10.1016/j.gendis.2024.101307
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