BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.06.004
{"title":"ProteoCure: A European network to fine-tune the proteome","authors":"","doi":"10.1016/j.biochi.2024.06.004","DOIUrl":"10.1016/j.biochi.2024.06.004","url":null,"abstract":"<div><div>Proteins are essential molecular actors in every cellular process. From their synthesis to their degradation, they are subject to continuous quality control mechanisms to ensure that they fulfil cellular needs in proper and timely fashion.</div><div>Proteostasis is a key process allowing cells or organisms to maintain an appropriate but dynamic equilibrium of their proteome (the ensemble of all their proteins). It relies on multiple mechanisms that together control the level, fate and function of individual proteins, and ensure elimination of abnormal ones. The proteostasis network is essential for development and adaptation to environmental changes or challenges. Its dysfunctions can lead to accumulation of deleterious proteins or, conversely, to excessive degradation of beneficial ones, and are implicated in many diseases such as cancers, neurodegeneration, or developmental and aging disorders. Manipulating this network to control abundance of selected target proteins is therefore a strategy with enormous therapeutic or biotechnological potential.</div><div>The ProteoCure COST Action gathers more than 350 researchers and their teams (31 countries represented) from the academic, clinical, and industrial sectors, who share the conviction that our understanding of proteostasis is mature enough to develop novel and highly specific therapies based on selective tuning of protein levels. Towards this objective, the Action organizes community-building activities to foster synergies among its participants and reinforce training of the next generation of European researchers. Its ambition is to function as a knowledge-based network and a creative exchange hub on normal and pathologic proteostasis, focusing on developing innovative tools modulating the level of specific protein(s).</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 4-9"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141433650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.07.007
Silje Kathrine Larsen , Åse K. Bekkelund , Nina Glomnes , Thomas Arnesen , Henriette Aksnes
{"title":"Assessing N-terminal acetylation status of cellular proteins via an antibody specific for acetylated methionine","authors":"Silje Kathrine Larsen , Åse K. Bekkelund , Nina Glomnes , Thomas Arnesen , Henriette Aksnes","doi":"10.1016/j.biochi.2024.07.007","DOIUrl":"10.1016/j.biochi.2024.07.007","url":null,"abstract":"<div><div><em>N</em>-terminal acetylation is being recognized as a factor affecting protein lifetime and proteostasis. It is a modification where an acetyl group is added to the <em>N</em>-terminus of proteins, and this occurs in 80 % of the human proteome. <em>N</em>-terminal acetylation is catalyzed by enzymes called <em>N</em>-terminal acetyltransferases (NATs). The various NATs acetylate different <em>N</em>-terminal amino acids, and methionine is a known target for some of the NATs. Currently, the acetylation status of most proteins can only be assessed with a limited number of methods, including mass spectrometry, which although powerful and robust, remains laborious and can only survey a fraction of the proteome. We here present testing of an antibody that was developed to specifically recognize Nt-acetylated methionine-starting proteins. We have used dot blots with synthetic acetylated and non-acetylated peptides in addition to protein analysis of lysates from NAT knockout cell lines to assess the specificity and application of this anti-Nt-acetylated methionine antibody (anti-NtAc-Met). Our results demonstrate that this antibody is indeed NtAc-specific and further show that it has selectivity for some subtypes of methionine-starting <em>N</em>-termini, specifically potential substrates of the NatC, NatE and NatF enzymes. We propose that this antibody may be a powerful tool to identify NAT substrates or to analyse changes in <em>N</em>-terminal acetylation for specific cellular proteins of interest.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 113-120"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.04.003
{"title":"PA28γ, the ring that makes tumors invisible to the immune system?","authors":"","doi":"10.1016/j.biochi.2024.04.003","DOIUrl":"10.1016/j.biochi.2024.04.003","url":null,"abstract":"<div><div><span><span><span>PA28γ is a proteasomal interactor whose main and most known function is to stimulate the hydrolytic activity of the 20 S </span>proteasome<span> independently of ubiquitin and ATP. Unlike its two paralogues, PA28α and PA28β, PA28γ is largely present in the nuclear compartment and plays pivotal functions in important pathways such as cellular division, apoptosis, neoplastic transformation, chromatin structure and organization, fertility, </span></span>lipid metabolism, and </span>DNA repair<span> mechanisms. Although it is known that a substantial fraction of PA28γ is found in the cell in a free form (i.e. not associated with 20 S), almost all of the studies so far have focused on its ability to modulate proteasomal enzymatic activities<span><span><span>. In this respect, the ability of PA28γ to strongly stimulate degradation of proteins, especially if intrinsically disordered and therefore devoid of three-dimensional tightly folded structure, appears to be the main molecular mechanism underlying its multiple biological effects. Initial studies, conducted more than 20 years ago, came to the conclusion that among the many </span>biological functions<span><span> of PA28γ, the immunological ones were rather limited and circumscribed. In this review, we focus on recent evidence showing that PA28γ fulfills significant functions in cell-mediated acquired immunity, with a particular role in attenuating </span>MHC class I </span></span>antigen presentation, especially in relation to neoplastic transformation and autoimmune diseases.</span></span></div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 136-147"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140778475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.04.001
{"title":"Kallikrein-related peptidase's significance in Alzheimer's disease pathogenesis: A comprehensive survey","authors":"","doi":"10.1016/j.biochi.2024.04.001","DOIUrl":"10.1016/j.biochi.2024.04.001","url":null,"abstract":"<div><div><span><span>Alzheimer's disease (AD) and related dementias constitute an important global health challenge. Detailed understanding of the multiple molecular mechanisms underlying their pathogenesis constitutes a clue for the management of the disease. Kallikrein-related peptidases (KLKs), a lead family of </span>serine proteases<span>, have emerged as potential biomarkers and therapeutic targets in the context of AD and associated cognitive decline. Hence, KLKs were proposed to display multifaceted impacts influencing various aspects of </span></span>neurodegeneration<span>, including amyloid-beta aggregation, tau pathology, neuroinflammation<span>, and synaptic dysfunction. We propose here a comprehensive survey to summarize recent findings, providing an overview of the main kallikreins implicated in AD pathophysiology<span> namely KLK8, KLK6 and KLK7<span>. We explore the interplay between KLKs and key AD molecular pathways, shedding light on their significance as potential biomarkers for early disease detection. We also discuss their pertinence as therapeutic targets for disease-modifying interventions to develop innovative therapeutic strategies aimed at halting or ameliorating the progression of AD and associated dementias.</span></span></span></span></div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 77-90"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.03.013
{"title":"Cathepsin D inhibition during neuronal differentiation selectively affects individual proteins instead of overall protein turnover","authors":"","doi":"10.1016/j.biochi.2024.03.013","DOIUrl":"10.1016/j.biochi.2024.03.013","url":null,"abstract":"<div><div>Cathepsin D (CTSD) is a lysosomal aspartic protease and its inherited deficiency causes a severe pediatric neurodegenerative disease called neuronal ceroid lipofuscinosis (NCL) type 10. The lysosomal dysfunction in the affected patients leads to accumulation of undigested lysosomal cargo especially in none-dividing cells, such as neurons, resulting in death shortly after birth. To explore which proteins are mainly affected by the lysosomal dysfunction due to CTSD deficiency, Lund human mesencephalic (LUHMES) cells, capable of inducible dopaminergic neuronal differentiation, were treated with Pepstatin A. This inhibitor of “acidic” aspartic proteases caused accumulation of acidic intracellular vesicles in differentiating LUHMES cells. Pulse-chase experiments involving stable isotope labelling with amino acids in cell culture (SILAC) with subsequent mass-spectrometric protein identification and quantification were performed. By this approach, we studied the degradation and synthesis rates of 695 and 680 proteins during early and late neuronal LUHMES differentiation, respectively. Interestingly, lysosomal bulk proteolysis was not altered upon Pepstatin A treatment. Instead, the protease inhibitor selectively changed the turnover of individual proteins. Especially proteins belonging to the mitochondrial energy supply system were differentially degraded during early and late neuronal differentiation indicating a high energy demand as well as stress level in LUHMES cells treated with Pepstatin A.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 35-48"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140327448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.02.006
{"title":"Cytoskeletal β-tubulin and cysteine cathepsin L deregulation by SARS-CoV-2 spike protein interaction with the neuronal model cell line SH-SY5Y","authors":"","doi":"10.1016/j.biochi.2024.02.006","DOIUrl":"10.1016/j.biochi.2024.02.006","url":null,"abstract":"<div><div>SARS-CoV-2 mainly infects the respiratory tract but can also target other organs, including the central nervous system. While it was recently shown that cells of the blood-brain-barrier are permissive to SARS-CoV-2 infection <em>in vitro</em>, it remains debated whether neurons can be infected. In this study, we demonstrate that vesicular stomatitis virus particles pseudotyped with the spike protein of SARS-CoV-2 variants WT, Alpha, Delta and Omicron enter the neuronal model cell line SH-SY5Y. Cell biological analyses of the pseudo-virus treated cultures showed marked alterations in microtubules of SH-SY5Y cells. Because the changes in β-tubulin occurred in most cells, but only few were infected, we further asked whether interaction of the cells with spike protein might be sufficient to cause molecular and structural changes. For this, SH-SY5Y cells were incubated with trimeric spike proteins for time intervals of up to 24 h. CellProfiler™-based image analyses revealed changes in the intensities of microtubule staining in spike protein-incubated cells. Furthermore, expression of the spike protein-processing protease cathepsin L was found to be up-regulated by wild type, Alpha and Delta spike protein pseudotypes and cathepsin L was found to be secreted from spike protein-treated cells. We conclude that the mere interaction of the SARS-CoV-2 with neuronal cells can affect cellular architecture and proteolytic capacities. The molecular mechanisms underlying SARS-CoV-2 spike protein induced cytoskeletal changes in neuronal cells remain elusive and require future studies.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 49-61"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140023683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiochimiePub Date : 2024-11-01DOI: 10.1016/j.biochi.2024.03.007
{"title":"Thrombin stories in the gut","authors":"","doi":"10.1016/j.biochi.2024.03.007","DOIUrl":"10.1016/j.biochi.2024.03.007","url":null,"abstract":"<div><div><span><span><span>Many studies have demonstrated the involvement of proteases in </span>gut physiology<span> and pathophysiology<span> over the recent years. Among them, thrombin has appeared for a long time as an old player only involved in blood clotting upon </span></span></span>tissue injury. The fact that </span>thrombin receptors (Protease-Activated Receptors-1 and -4) are expressed and functional in almost all cell types of the gut, contributing to barrier, immune or motility functions, suggested that thrombin could actually be at the crossroad of intestinal physiology. Recent work has unraveled the constitutive release of active thrombin by intestinal epithelial cells, opening new research avenues on the role of thrombin in the gut. These roles are considered in the present review, as well as the regulation of thrombin in the gut. The potential of thrombin as a target for treatments of intestinal pathologies is also discussed here.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"226 ","pages":"Pages 107-112"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140195304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}