Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Язык: Английский

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How epigenetics impacts on human diseases

European Journal of Internal Medicine, Год журнала: 2023, Номер 114, С. 15 - 22

Опубликована: Июнь 3, 2023

Epigenetics is a rapidly growing field of biology that studies the changes in gene expression are not due to alterations DNA sequence but rather chemical modifications and its associated proteins. Epigenetic mechanisms can profoundly influence expression, cell differentiation, tissue development, disease susceptibility. Understanding epigenetic essential elucidate underlying increasingly recognized role environmental lifestyle factors health intergenerational transmission phenotypes. Recent suggest epigenetics may be critical various diseases, from cardiovascular cancer neurodevelopmental neurodegenerative disorders. potentially reversible could provide new therapeutic avenues for treating these diseases using modulators. Moreover, insight into pathogenesis biomarkers diagnosis risk stratification. Nevertheless, interventions have potential unintended consequences lead increased risks unexpected outcomes, such as adverse drug reactions, developmental abnormalities, cancer. Therefore, rigorous minimize with therapies develop safe effective improving human health. This article provides synthetic historical view origin some most relevant achievements.

Язык: Английский

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HuR as a molecular target for cancer therapeutics and immune-related disorders

Advanced Drug Delivery Reviews, Год журнала: 2022, Номер 188, С. 114442 - 114442

Опубликована: Июль 8, 2022

Язык: Английский

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PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade

Cell Reports, Год журнала: 2022, Номер 38(13), С. 110582 - 110582

Опубликована: Март 1, 2022

Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies expected to enhance response rates overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI induces a strong anti-tumor T cell immunity restrains tumor growth in vivo by increasing infiltration. PRMT7-deficient B16.F10 melanoma exhibits increased expression genes interferon pathway, antigen presentation, chemokine signaling. deficiency or SGC3027 results reduced DNMT expression, loss DNA methylation regulatory regions endogenous retroviral elements (ERVs) causing their expression. cells increase RIG-I MDA5 reduction H4R3me2s repressive histone mark at gene promoters. Our findings identify as RIG-I, MDA5, ERV-double-stranded RNA (dsRNA) ligands, facilitating escape restrain growth.

Язык: Английский

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Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives

Molecular Medicine, Год журнала: 2023, Номер 29(1)

Опубликована: Июль 6, 2023

Abstract The metabolism of glucose and lipids is essential for energy production in the body, dysregulation metabolic pathways these molecules implicated various acute chronic diseases, such as type 2 diabetes, Alzheimer’s disease, atherosclerosis (AS), obesity, tumor, sepsis. Post-translational modifications (PTMs) proteins, which involve addition or removal covalent functional groups, play a crucial role regulating protein structure, localization function, activity. Common PTMs include phosphorylation, acetylation, ubiquitination, methylation, glycosylation. Emerging evidence indicates that are significant modulating lipid by modifying key enzymes proteins. In this review, we summarize current understanding regulatory mechanisms metabolism, with focus on their involvement disease progression associated aberrant metabolism. Furthermore, discuss future prospects PTMs, highlighting potential gaining deeper insights into related diseases.

Язык: Английский

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PRMT6 methylation of STAT3 regulates tumor metastasis in breast cancer

Cell Death and Disease, Год журнала: 2023, Номер 14(10)

Опубликована: Окт. 9, 2023

Overcoming distant metastasis stands as a paramount challenge in enhancing the outcomes of breast cancer treatments. Thus, delving deeper into comprehending intricate mechanisms underlying becomes imperative, offering potential avenues for pioneering therapeutic approaches. PRMT6, an arginine N-methyltransferase, possesses ability to methylate both histone and non-histone proteins. It has been reported that methylation proteins impacts their cellular localization, stability, activation, consequently influencing tumor progression. However, extent which PRMT6-mediated protein influences cell metastasis, particularly context cancer, remains elusive. In this study, we established PRMT6 exerted positive regulatory influence on through vivo vitro experiments. Mechanistically, innovatively revealed asymmetrically di-methylated STAT3 at 729 (STAT3 R729me2a). This modification proved indispensable STAT3's membrane its interaction with JAK2, Y705 phosphorylation, PRMT6-driven metastasis. From clinical perspective, unearthed promising R729me2a robust prognostic marker predicting overall survival time patients. terms intervention, demonstrated significant capability inhibitor, EPZ020411, curtail vitro. sum, our study unveils pivotal biological role underscores prospective utility inhibitors effective strategies against STAT3-driven metastatic cancer.

Язык: Английский

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Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance

Drug Resistance Updates, Год журнала: 2023, Номер 72, С. 101016 - 101016

Опубликована: Ноя. 3, 2023

Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic methylation, which regulates various biological and pathological processes, as result, they attractive therapeutic targets overcoming anti-cancer drug resistance. The ongoing small molecules targeting PRMTs has resulted generation chemical probes modulating most facilitated clinical treatment advanced oncology targets, including PRMT1 PRMT5. In this review, we summarize mechanisms underlying protein methylation roles specific driving Furthermore, highlight potential implications PRMT inhibitors decreasing promote formation maintenance drug-tolerant cells via several mechanisms, altered efflux transporters, autophagy, DNA damage repair, stem cell-related function, epithelial-mesenchymal transition, disordered tumor microenvironment. Multiple preclinical trials have demonstrated that inhibitors, particularly PRMT5 can sensitize drugs, chemotherapeutic, targeted therapeutic, immunotherapeutic agents. Combining with existing will be promising approach enhanced knowledge complex functions guide future may help identify new indications.

Язык: Английский

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Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Chemical Reviews, Год журнала: 2024, Номер 124(5), С. 2805 - 2838

Опубликована: Фев. 19, 2024

Post-translational modifications (PTMs) endow proteins with new properties to respond environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds distinct types PTMs have been observed in a wide range from bacteria, archaea, and eukarya. To identify roles these PTMs, scientists applied various approaches. However, high dynamics, low stoichiometry, crosstalk between make it almost impossible obtain homogeneously modified for characterization site-specific effect individual PTM on target proteins. solve this problem, genetic code expansion (GCE) strategy has introduced into field studies. Instead modifying after translation, GCE incorporates amino acids during thus generating site-specifically at positions. In review, we summarize systems orthogonal translation installation PTMs.

Язык: Английский

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Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

Cancer Communications, Год журнала: 2024, Номер 44(6), С. 601 - 636

Опубликована: Май 7, 2024

Abstract Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity called “cold” which unresponsive to immunotherapy, and opposite “hot” tumors. Immune suppressive cells (ISCs) refer can inhibit response such as tumor‐associated macrophages (TAMs), myeloid‐derived suppressor (MDSCs), regulatory T (Treg) so on. The more ISCs infiltrated, weaker tumor, showing characteristics tumor. dysfunction tumor microenvironment (TME) may play essential roles insensitive therapeutic reaction. Previous studies found that epigenetic mechanisms an important role regulation ISCs. Regulating be a new approach transforming into Here, we focused on function TME discussed how epigenetics is involved regulating In addition, summarized by drugs convert immunotherapy‐insensitive immunotherapy‐sensitive would innovative tendency for future immunotherapy

Язык: Английский

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Overview of the development of protein arginine methyltransferase modulators: Achievements and future directions

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 267, С. 116212 - 116212

Опубликована: Фев. 10, 2024

Язык: Английский

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