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Current Opinion in Structural Biology Feb 2024During protein synthesis, the growing nascent peptide chain moves inside the polypeptide exit tunnel of the ribosome from the peptidyl transferase center towards the... (Review)
Review
During protein synthesis, the growing nascent peptide chain moves inside the polypeptide exit tunnel of the ribosome from the peptidyl transferase center towards the exit port where it emerges into the cytoplasm. The ribosome defines the unique energy landscape of the pioneering round of protein folding. The spatial confinement and the interactions of the nascent peptide with the tunnel walls facilitate formation of secondary structures, such as α-helices. The vectorial nature of protein folding inside the tunnel favors local intra- and inter-molecular interactions, thereby inducing cotranslational folding intermediates that do not form upon protein refolding in solution. Tertiary structures start to fold in the lower part of the tunnel, where interactions with the ribosome destabilize native protein folds. The present review summarizes the recent progress in understanding the driving forces of nascent protein folding inside the tunnel and at the surface of the ribosome.
Topics: Protein Folding; Ribosomes; Protein Biosynthesis; Proteins; Peptides
PubMed: 38071940
DOI: 10.1016/j.sbi.2023.102740 -
Frontiers in Immunology 2023O-GlcNAcylation is a post-translational modification of proteins that involves the addition of O-GlcNAc to serine or threonine residues of nuclear or cytoplasmic... (Review)
Review
O-GlcNAcylation is a post-translational modification of proteins that involves the addition of O-GlcNAc to serine or threonine residues of nuclear or cytoplasmic proteins, catalyzed by O-GlcNAc transferase (OGT). This modification is highly dynamic and can be reversed by O-GlcNAcase (OGA). O-GlcNAcylation is widespread in the immune system, which engages in multiple physiologic and pathophysiologic processes. There is substantial evidence indicating that both the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation are critically involved in regulating immune cell function. However, the precise role of O-GlcNAcylation in the immune system needs to be adequately elucidated. This review offers a thorough synopsis of the present research on protein O-GlcNAcylation, accentuating the molecular mechanisms that control immune cells' growth, maturation, and performance this PTM.
Topics: Acetylglucosaminidase; Cell Proliferation; Cell Cycle; Protein Processing, Post-Translational; Research Design
PubMed: 37675125
DOI: 10.3389/fimmu.2023.1209970 -
Biomolecules Mar 2024Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement... (Review)
Review
Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.
Topics: Humans; Diabetes Mellitus, Type 2; Protein Processing, Post-Translational; Phosphorylation; Glycosylation; Sumoylation
PubMed: 38540730
DOI: 10.3390/biom14030310 -
Molecular Cell Oct 2023Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent...
Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.
Topics: Mitochondria; Triage; Mitochondrial Proteins; Ribosomes; Protein Biosynthesis; Oxidative Phosphorylation; Ribosomal Proteins
PubMed: 37751741
DOI: 10.1016/j.molcel.2023.09.001 -
Cell Death & Disease Oct 2023Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on... (Review)
Review
Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on substrates in order to regulate cellular processes. LUBAC comprised by HOIP, HOIL-1L, and SHARPIN as a sole E3 ligase catalyzes the generation of linear ubiquitin chains, and it is simultaneously adjusted by deubiquitinases such as OTULIN and CYLD. Several studies have shown that gene mutation of linear ubiquitination in mice accompanied by different modalities of cell death would develop relative diseases. Cell death is a fundamental physiological process and responsible for embryonic development, organ maintenance, and immunity response. Therefore, it is worth speculating that linear ubiquitin mediated signaling pathway would participate in different diseases. The relative literature search was done from core collection of electronic databases such as Web of Science, PubMed, and Google Scholar using keywords about main regulators of linear ubiquitination pathway. Here, we summarize the regulatory mechanism of linear ubiquitination on cellular signaling pathway in cells with apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Intervening generation of linear ubiquitin chains in relative signaling pathway to regulate cell death might provide novel therapeutic insights for various human diseases.
Topics: Animals; Humans; Mice; Ubiquitination; Ubiquitin; Protein Processing, Post-Translational; Ubiquitin-Protein Ligases; Ubiquitins; Cell Death; NF-kappa B
PubMed: 37813853
DOI: 10.1038/s41419-023-06183-3 -
Cell Reports Dec 2023Tumor-associated myeloid cells modulate the tumor microenvironment and affect tumor progression. Type I interferon (IFN-I) has multiple effects on tumors and immune...
Tumor-associated myeloid cells modulate the tumor microenvironment and affect tumor progression. Type I interferon (IFN-I) has multiple effects on tumors and immune response, and ubiquitin-specific peptidase 18 (USP18) functions as a negative regulator of IFN-I signal transduction. This study aims to examine the function of IFN-I in myeloid cells during tumor progression. Here, we show that deletion of USP18 in myeloid cells suppresses tumor progression. Enhanced IFN-I signaling and blocked USP18 expression prompt downregulation of colony stimulating factor 1 receptor (CSF1R) and polarization of tumor-associated macrophages toward pro-inflammatory phenotypes. Further in vitro experiments reveal that downregulation of CSF1R is mediated by ubiquitin-proteasome degradation via E3 ligase neural precursor cell-expressed, developmentaly downregulated 4 (NEDD4) and the IFN-induced increase in ubiquitin E2 ubiquitin-conjugating enzyme H5. USP18 impairs ubiquitination and subsequent degradation of CSF1R by interrupting NEDD4 binding to CSF1R. These results reveal a previously unappreciated role of IFN-I in macrophage polarization by regulating CSF1R via USP18 and suggest targeting USP18 in myeloid-lineage cells as an effective strategy for IFN-based therapies.
Topics: Tumor-Associated Macrophages; Signal Transduction; Receptor Protein-Tyrosine Kinases; Ubiquitin; Ubiquitination
PubMed: 38100351
DOI: 10.1016/j.celrep.2023.113560 -
Targeting succinylation-mediated metabolic reprogramming as a potential approach for cancer therapy.Biomedicine & Pharmacotherapy =... Dec 2023Metabolic reprogramming is a common hallmark of cancers and involves alterations in many metabolic pathways during tumor initiation and progression. However, the... (Review)
Review
Metabolic reprogramming is a common hallmark of cancers and involves alterations in many metabolic pathways during tumor initiation and progression. However, the cancer-specific modulation of metabolic reprogramming requires further elucidation. Succinylation, a newly identified protein posttranslational modification (PTM), participates in many cellular processes by transferring a succinyl group to a residue of the target protein, which is related to various pathological disorders including cancers. In recent years, there has been a gradual increase in the number of studies on the regulation of tumors by protein succinylation. Notably, accumulating evidence suggests that succinylation can mediate cancer cell metabolism by altering the structure or activity of metabolism-related proteins and plays vital roles in metabolic reprogramming. Furthermore, some antitumor drugs have been linked to succinylation-mediated tumor-associated metabolism. To better elucidate lysine succinylation mediated tumor metabolic reprogramming, this review mainly summarizes recent studies on the regulation and effects of protein succinylation in tumors, focusing on the metabolic regulation of tumorigenesis and development, which will provide new directions for cancer diagnosis as well as possible therapeutic targets.
Topics: Metabolic Networks and Pathways; Protein Processing, Post-Translational; Neoplasms
PubMed: 37852104
DOI: 10.1016/j.biopha.2023.115713 -
Journal of Cellular and Molecular... Apr 2024The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria... (Review)
Review
The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria and targeted treatment approaches in clinical practice. Ongoing research is gradually unravelling the pathogenesis of diabetic cardiomyopathy, with a particular emphasis on investigating various post-translational modifications. These modifications dynamically regulate protein function in response to changes in the internal and external environment, and their disturbance of homeostasis holds significant relevance for the development of chronic ailments. This review provides a comprehensive overview of the common post-translational modifications involved in the initiation and progression of diabetic cardiomyopathy, including O-GlcNAcylation, phosphorylation, methylation, acetylation and ubiquitination. Additionally, the review discusses drug development strategies for targeting key post-translational modification targets, such as agonists, inhibitors and PROTAC (proteolysis targeting chimaera) technology that targets E3 ubiquitin ligases.
Topics: Humans; Diabetic Cardiomyopathies; Protein Processing, Post-Translational; Ubiquitination; Phosphorylation; Ubiquitin-Protein Ligases; Diabetes Mellitus
PubMed: 38494853
DOI: 10.1111/jcmm.18158 -
Trends in Neurosciences Oct 2023The processes of mRNA export from the nucleus and subsequent mRNA translation in the cytoplasm are of particular relevance in eukaryotic cells. In highly polarised cells... (Review)
Review
The processes of mRNA export from the nucleus and subsequent mRNA translation in the cytoplasm are of particular relevance in eukaryotic cells. In highly polarised cells such as neurons, finely-tuned molecular regulation of these processes serves to safeguard the spatiotemporal fidelity of gene expression. Nonsense-mediated mRNA decay (NMD) is a cytoplasmic translation-dependent quality control process that regulates gene expression in a wide range of scenarios in the nervous system, including neurodevelopment, learning, and memory formation. Moreover, NMD dysregulation has been implicated in a broad range of neurodevelopmental and neurodegenerative disorders. We discuss how NMD and related aspects of mRNA translation regulate key neuronal functions and, in particular, we focus on evidence implicating these processes in the molecular pathogenesis of neurodegeneration. Finally, we discuss the therapeutic potential and challenges of targeting mRNA translation and NMD across the spectrum of largely untreatable neurological diseases.
Topics: Humans; Nonsense Mediated mRNA Decay; Protein Biosynthesis; Neurons
PubMed: 37543480
DOI: 10.1016/j.tins.2023.07.001 -
Trends in Cancer Aug 2023Immunotherapy has been a paradigm shift in cancer treatment to produce durable responses. Unfortunately, most cancers do not respond to current immunotherapies, and...
Immunotherapy has been a paradigm shift in cancer treatment to produce durable responses. Unfortunately, most cancers do not respond to current immunotherapies, and thus, exploring novel mechanisms is crucial. Emerging data now demonstrate that protein modification by the small ubiquitin-like modifiers (SUMO) is a novel target to activate antitumor immunity.
Topics: Humans; Sumoylation; Small Ubiquitin-Related Modifier Proteins; Protein Processing, Post-Translational; Neoplasms
PubMed: 37179168
DOI: 10.1016/j.trecan.2023.04.010