FEBS Letters最新文献

{"title":"Leveraging current insights on IL‐10‐producing dendritic cells for developing effective immunotherapeutic approaches","authors":"Konstantina Morali, Gloria Giacomello, Michela Vuono, Silvia Gregori","doi":"10.1002/1873-3468.15017","DOIUrl":"https://doi.org/10.1002/1873-3468.15017","url":null,"abstract":"Dendritic cells (DC) are professional antigen‐presenting cells involved in promoting and controlling immune responses. Different subsets of DC, named tolerogenic (tol)DC, play a critical role in the maintenance of tissue homeostasis and in fostering tolerance. These unique skills make tolDC especially attractive for strategies aimed at re‐establishing/inducing tolerance in immune‐mediated conditions. The generation of potent tolDC <jats:italic>in vitro</jats:italic> from peripheral blood monocytes has seen remarkable advancements. TolDC modulate T cell dynamics by favoring regulatory T cells (Tregs) and curbing effector/pathogenic T cells. Among the several methods developed for in vitro tolDC generation, IL‐10 conditioning has been proven to be the most efficient, as IL‐10‐modulated tolDC were demonstrated to promote Tregs with the strongest suppressive activities. Investigating the molecular, metabolic, and functional profiles of tolDC uncovers essential pathways that facilitate their immunoregulatory functions. This Review provides an overview of current knowledge on the role of tolDC in health and disease, focusing on IL‐10 production, functional characterization of <jats:italic>in vitro</jats:italic> generated tolDC, molecular and metabolic changes occurring in tolDC induced by tolerogenic agents, clinical applications of tolDC‐based therapy, and finally new perspectives in the generation of effective tolDC.","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue","authors":"Caroline Harter, Frédéric Melin, Franziska Hoeser, Petra Hellwig, Daniel Wohlwend, Thorsten Friedrich","doi":"10.1002/1873-3468.15013","DOIUrl":"https://doi.org/10.1002/1873-3468.15013","url":null,"abstract":"Respiratory complex I is a central metabolic enzyme coupling NADH oxidation and quinone reduction with proton translocation. Despite the knowledge of the structure of the complex, the coupling of both processes is not entirely understood. Here, we use a combination of site‐directed mutagenesis, biochemical assays, and redox‐induced FTIR spectroscopy to demonstrate that the quinone chemistry includes the protonation and deprotonation of a specific, conserved aspartic acid residue in the quinone binding site (D325 on subunit NuoCD in <jats:italic>Escherichia coli</jats:italic>). Our experimental data support a proposal derived from theoretical considerations that deprotonation of this residue is involved in triggering proton translocation in respiratory complex I.","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA Modifications Shape Hematopoietic Stem Cell Aging: Beyond the Code","authors":"Inge van der Werf, Jenna Sneifer, Catriona Jamieson","doi":"10.1002/1873-3468.15014","DOIUrl":"https://doi.org/10.1002/1873-3468.15014","url":null,"abstract":"Hematopoietic system aging is characterized by both hematopoietic stem cell (HSC) and niche degeneration resulting in myeloid lineage-biased differentiation, reduced B cell and T cell lymphopoiesis, increased HSC mobilization, and fat deposition in the bone marrow. Both alterations in RNA splicing and editing during HSC aging contribute to increased myeloid lineage skewing and inflammation-responsive transcription factors, underscoring the importance of epitranscriptomic mechanisms in the acquisition of an age-related phenotype.","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox medicine: from cellular targets to systems physiology and therapeutics","authors":"Ana Ledo,&nbsp;Bárbara S. Rocha","doi":"10.1002/1873-3468.15005","DOIUrl":"https://doi.org/10.1002/1873-3468.15005","url":null,"abstract":"&lt;p&gt;Biomedical research has long been dedicated to elucidating the determinants of human health and disease. The interaction between intrinsic and environmental factors that affect the metabolic, immune, nervous, and endocrine systems has been the focus of many efforts in the field. Yet, redox signaling, which involves the fine modulation of molecular pathways by free radicals and oxidants, is emerging as a unifying theme in the pathophysiology of human diseases [&lt;span&gt;[1, 2]&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Biological oxidants are a chemically and biologically diverse group of molecules derived from molecular oxygen, nitrogen, or sulfur (although this could be extended to include other elements such as carbon, selenium, halogens, and electrophile species that undergo redox reactions) with critical signaling functions under physiological conditions, ensuring what has been coined by Helmut Sies as oxidative eustress [&lt;span&gt;[3]&lt;/span&gt;]. Dysregulation of redox homeostasis results in supra-physiological concentrations of these species, which establish non-specific reactions with biomolecules and generate other, more reactive species with the ability to react indiscriminately with most biomolecules, producing what is commonly refered to as oxidative (dis)stress [&lt;span&gt;[4]&lt;/span&gt;]. The transition from oxidative eustress to oxidative distress is a common observation in several pathophysiological conditions [&lt;span&gt;[3, 4]&lt;/span&gt;]. As such, cells strategically employ several defense systems, including enzymes and low molecular weight antioxidants, to maintain redox homeostasis. Sensing systems detect shifts from the steady-state oxidant level and initiate appropriate defense strategies. Important redox hubs worth mentioning include NRF2, NF-κB, HIF, ERR, FOXO, PGC1α, AMPK, GAPDH, and UCP, all of which are regulated via oxidation of Cys residues either on adaptor proteins or on the transcription factor itself (reviewed in [&lt;span&gt;[5, 6]&lt;/span&gt;]).&lt;/p&gt;&lt;p&gt;Superoxide radical (&lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;mrow&gt;\u0000 &lt;msubsup&gt;\u0000 &lt;mi&gt;O&lt;/mi&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mo&gt;−&lt;/mo&gt;\u0000 &lt;mo&gt;⋅&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msubsup&gt;\u0000 &lt;/mrow&gt;&lt;/math&gt;) and hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;) are two important examples of biological oxidants produced by tightly controlled enzymatic reactions, notably NADH- (mitochondria) and NADPH-dependent systems (including NADPH oxidases—NOX) as well as superoxide dismutase (SOD), and are promptly decomposed by catalase, peroxiredoxins and phase II enzymes (discussed in [&lt;span&gt;[7]&lt;/span&gt;]). The redox signaling role of H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; is mainly the result of oxidation of specific Cys residues to sulfenic acid and redox relay via peroxiredoxins [&lt;span&gt;[8-10]&lt;/span&gt;]. This ultimately results in the modulation of metabolism, phosphorylation cascades, regulation of transcription, and other ","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.15005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A primer on single-cell RNA-seq analysis using dendritic cells as a case study.","authors":"Giulia Protti, Roberto Spreafico","doi":"10.1002/1873-3468.15009","DOIUrl":"https://doi.org/10.1002/1873-3468.15009","url":null,"abstract":"<p><p>Recent advances in single-cell (sc) transcriptomics have revolutionized our understanding of dendritic cells (DCs), pivotal players of the immune system. ScRNA-sequencing (scRNA-seq) has unraveled a previously unrecognized complexity and heterogeneity of DC subsets, shedding light on their ontogeny and specialized roles. However, navigating the rapid technological progress and computational methods can be daunting for researchers unfamiliar with the field. This review aims to provide immunologists with a comprehensive introduction to sc transcriptomic analysis, offering insights into recent developments in DC biology. Addressing common analytical queries, we guide readers through popular tools and methodologies, supplemented with references to benchmarks and tutorials for in-depth understanding. By examining findings from pioneering studies, we illustrate how computational techniques have expanded our knowledge of DC biology. Through this synthesis, we aim to equip researchers with the necessary tools and knowledge to navigate and leverage scRNA-seq for unraveling the intricacies of DC biology and advancing immunological research.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIN1 is a novel interaction partner and a negative upstream regulator of the transcription factor NFIB.","authors":"Sinem Saritas Erdogan, Ahmet Erdal Yilmaz, Asli Kumbasar","doi":"10.1002/1873-3468.15010","DOIUrl":"https://doi.org/10.1002/1873-3468.15010","url":null,"abstract":"<p><p>NFIB is a transcription factor of the Nuclear Factor One (NFI) family that is essential for embryonic development. Post-translational control of NFIB or its upstream regulators have not been well characterized. Here, we show that PIN1 binds NFIB in a phosphorylation-dependent manner, via its WW domain. PIN1 interacts with the well-conserved N-terminal domains of all NFIs. Moreover, PIN1 attenuates the transcriptional activity of NFIB; this attenuation requires substrate binding by PIN1 but not its isomerase activity. Paradoxically, we found stabilization of NFIB by PIN1. We propose that PIN1 represses NFIB function not by regulating its abundance but by inducing a conformational change. These results identify NFIB as a novel PIN1 target and posit a role for PIN1 in post-translational regulation of NFIB and other NFIs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spontaneous and chaperone-assisted metal loading in the active site of protein phosphatase-1.","authors":"Gerd Van der Hoeven, Sarah Lemaire, Xinyu Cao, Zander Claes, Spyridoula Karamanou, Mathieu Bollen","doi":"10.1002/1873-3468.15012","DOIUrl":"https://doi.org/10.1002/1873-3468.15012","url":null,"abstract":"<p><p>Protein phosphatase PP1 has two active-site metals (Zn²⁺/Fe²⁺) that are essential for catalysis. However, when expressed in bacteria, PP1 has two Mn²⁺-ions in its active site, indicating that the incorporation of Zn²⁺/Fe²⁺ depends on additional eukaryotic component(s). Here, we used purified, metal-deficient PP1 to study metal incorporation. Fe²⁺ was incorporated spontaneously, but Zn²⁺ was not. Mn²⁺-incorporation at physiological pH depended on the co-expression of PP1 with PPP1R2 (Inhibitor-2) or PPP1R11 (Inhibitor-3), or a pre-incubation of PP1 at pH 4. We also demonstrate that PPP1R2 and PPP1R11 are Zn²⁺-binding proteins but are, by themselves, not able to load PP1 with Zn²⁺. Our data suggest that PPP1R2 and PPP1R11 function as metal chaperones for PP1 but depend on co-chaperone(s) and/or specific modification(s) for the transfer of associated Zn²⁺ to PP1.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.","authors":"Lishu Guo","doi":"10.1002/1873-3468.15008","DOIUrl":"https://doi.org/10.1002/1873-3468.15008","url":null,"abstract":"<p><p>The opening of the mitochondrial permeability transition pore (PTP), a Ca²⁺-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A shift in chromatin binding of phosphorylated p38 precedes transcriptional changes upon oxidative stress.","authors":"Carlos Camilleri-Robles, Paula Climent-Cantó, Palmira Llorens-Giralt, Cecilia C Klein, Florenci Serras, Montserrat Corominas","doi":"10.1002/1873-3468.15006","DOIUrl":"https://doi.org/10.1002/1873-3468.15006","url":null,"abstract":"<p><p>P38 mitogen-activated protein kinases are key in the regulation of the cellular response to stressors. P38 is known to regulate transcription, mRNA processing, stability, and translation. The transcriptional changes mediated by phosphorylated p38 (P-p38) in response to extracellular stimuli have been thoroughly analyzed in many tissues and organisms. However, the genomic localization of chromatin-associated P-p38 remains poorly understood. Here, we analyze the chromatin binding of activated P-p38 and its role in the response to reactive oxygen species (ROS) in Drosophila S2 cells. We found that P-p38 is already bound to chromatin in basal conditions. After ROS exposure, chromatin-associated P-p38 relocates towards genes involved in the recovery process. Our findings highlight the role of P-p38 dynamic chromatin binding in orchestrating gene expression responses to oxidative stress.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of sugar recognition by SCFFBS2 ubiquitin ligase involved in NGLY1 deficiency","authors":"Tadashi Satoh,&nbsp;Maho Yagi-Utsumi,&nbsp;Nozomi Ishii,&nbsp;Tsunehiro Mizushima,&nbsp;Hirokazu Yagi,&nbsp;Ryuichi Kato,&nbsp;Yuriko Tachida,&nbsp;Hiroaki Tateno,&nbsp;Ichiro Matsuo,&nbsp;Koichi Kato,&nbsp;Tadashi Suzuki,&nbsp;Yukiko Yoshida","doi":"10.1002/1873-3468.15003","DOIUrl":"10.1002/1873-3468.15003","url":null,"abstract":"<p>The cytosolic peptide:<i>N</i>-glycanase (PNGase) is involved in the quality control of <i>N</i>-glycoproteins via the endoplasmic reticulum-associated degradation (ERAD) pathway. Mutations in the gene encoding cytosolic PNGase (<i>NGLY1</i> in humans) cause NGLY1 deficiency. Recent findings indicate that the F-box protein FBS2 of the SCF^FBS2 ubiquitin ligase complex can be a promising drug target for NGLY1 deficiency. Here, we determined the crystal structure of bovine FBS2 complexed with the adaptor protein SKP1 and a sugar ligand, Man₃GlcNAc₂, which corresponds to the core pentasaccharide of <i>N</i>-glycan. Our crystallographic data together with NMR data revealed the structural basis of disparate sugar-binding specificities in homologous FBS proteins and identified a potential druggable pocket for <i>in silico</i> docking studies. Our results provide a potential basis for the development of selective inhibitors against FBS2 in NGLY1 deficiency.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}