FEBS Letters最新文献

{"title":"Function-driven design of a surrogate interleukin-2 receptor ligand.","authors":"Ziwei Tang, Zelin Cheng, Teng Li, Fulian Wang, Liangminghui Zhang, Xiuxiu He, Lili Liu, Wei Wang, Aibin Liang, Guang Yang","doi":"10.1002/1873-3468.70249","DOIUrl":"10.1002/1873-3468.70249","url":null,"abstract":"<p><p>Interleukin (IL) receptors play a pivotal role in immune regulation through coordinated interactions among multiple receptor subunits. Their cognate ligands, interleukins, orchestrate diverse immune responses by engaging distinct subunit combinations. Here, we developed a programmable IL-2 receptor surrogate ligand using a combinatorial bispecific agonist antibody strategy. By employing two complementary cell-based reporter systems that simultaneously monitor IL-2 receptor-mediated STAT5 activation and cell proliferation, we engineered a surrogate IL-2 receptor ligand that exhibits biased activation and differentiation of effector T and NK cells. This modular approach enables the development of tailored cytokine receptor surrogates with customized immunomodulatory functions.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":"1222-1236"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762495","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":"The interaction of PD-1/PD-L1 and its inhibition by anti-PD-L1 antibody at the single-molecule level.","authors":"Yonghui Zhang, Diego Pilati, Mingdong Dong, Kenneth A Howard","doi":"10.1002/1873-3468.70245","DOIUrl":"10.1002/1873-3468.70245","url":null,"abstract":"<p><p>Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint signaling and its blockade by checkpoint inhibitors are dependent on molecular interactions at the binding interface. In this work, the two complete complex structures in the protein native state of PD-1 with PD-L1, and the anti-PD-L1 antibody atezolizumab were investigated by atomic force microscopy (AFM) single-molecule force spectroscopy and predicted by AlphaFold modeling. AFM revealed that the PD-1/PD-L1 binding interface displayed greater stability than the atezolizumab/PD-L1 complex due to hydrogen bonding, while the hydrophobic effect enhanced binding flexibility at the atezolizumab/PD-L1 interface. The two complexes exhibited different bond lifetimes reflecting binding interface stability and transition distance related to the interface flexibility. This work provides relevant methodology to evaluate single-molecule macromolecular interactions. Impact statement Our research developed a novel and close-to-native physiological platform to evaluate protein interactions from structural, mechanical, and kinetic perspectives at the single-molecule level. This could be applied in the design of more effective checkpoint inhibitory molecules and provides relevant methodologies for evaluating single-molecule macromolecular interactions.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":"1237-1247"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741677","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":"Alternative polyadenylation releases PCBP1-mediated suppression of CFIm25 during macrophage differentiation.","authors":"María Del Pilar Mendoza-Martín, Salwa Mohd Mostafa, Atish Barua, Claire L Moore, Srimoyee Mukherjee","doi":"10.1002/1873-3468.70313","DOIUrl":"10.1002/1873-3468.70313","url":null,"abstract":"<p><p>CFIm25, a key component of the cleavage factor Im (CFIm) complex needed for mRNA 3' end processing, shows increased protein expression during monocyte-to-macrophage differentiation despite stable mRNA levels. We demonstrate that poly(C)-binding protein 1 (PCBP1) suppresses CFIm25 translation in monocytes by binding to its long 3' untranslated region (UTR). During differentiation, alternative polyadenylation generates a shorter CFIm25 3'UTR lacking PCBP1 binding sites. RNA immunoprecipitation confirms PCBP1 binding to the long 3'UTR, while ribosome association analysis shows enhanced ribosome recruitment upon PCBP1 depletion. PCBP1 knockdown increases CFIm25 protein in undifferentiated cells and induces macrophage differentiation markers without stimulation. These findings reveal how alternative polyadenylation controls CFIm25 expression during immune cell differentiation by modulating RNA-binding protein interactions and provide insight into post-transcriptional regulation of RNA processing factors. Impact statement This work reveals how a key regulator of mRNA processing is itself controlled through a previously uncharacterized mechanism during immune cell differentiation. Our findings provide insights into the molecular circuits governing macrophage development and identify potential therapeutic targets for inflammatory disorders where myeloid cell differentiation is dysregulated.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":"1199-1210"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13049703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147456567","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":"Hyperosmotic stress induces PARP1-mediated HPF1-dependent mono(ADP-ribosyl)ation.","authors":"Anna Georgina Kopasz, Mihály Mérey, Rebeka Vásárhelyi, Ramóna Pék, Victor Imburchia, László Henn, Adrián Kószó, Nicholas D Lakin, Ivan Ahel, Sébastien Huet, Ágnes Czibula, Gyula Timinszky","doi":"10.1002/1873-3468.70334","DOIUrl":"10.1002/1873-3468.70334","url":null,"abstract":"<p><p>While the downstream effectors of the hyperosmotic stress response are relatively well characterized, the primary molecular sensors responsible for initial stress detection remain poorly defined. In this study, we demonstrate that hyperosmotic stress triggers a rapid and transient mono(ADP-ribosyl)ation (MARylation). Beside MARylation, signs of acute genotoxicity are missing and CHK1 activation is observed only upon recovery from osmotic stress. Our data indicate that PARP1 catalyzes its own MARylation in an HPF1 co-factor dependent manner. Biochemical assays further demonstrate that the mono-ADP-ribose moiety is resistant to hydroxylamine treatment, which is a feature of HPF1-directed O-glycosidic bonds. Together, these findings support a model in which PARP1 acts as a sensor of chromatin structure changes induced by hyperosmotic stress leading to its autoMARylation.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581069","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":"Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.","authors":"Sahitya Ranjan Biswas, Porter L Tomsick, Alicia M Pickrell, Paul D Morton","doi":"10.1002/1873-3468.70335","DOIUrl":"10.1002/1873-3468.70335","url":null,"abstract":"<p><p>Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581048","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":"The role and implications of mammalian cellular circadian entrainment","authors":"Priya Crosby","doi":"10.1002/1873-3468.70223","DOIUrl":"10.1002/1873-3468.70223","url":null,"abstract":"<p>The ability to align circadian phase to specific cues, or ‘entrainment’, is a defining feature of a circadian rhythm. Entrainment is critical for useful circadian function, as it enables organisms to determine the specific time of day to perform temporally restricted behavioural and physiological activities, ranging from sleep to cell division. While mammals have long been known to entrain their circadian rhythm, recent work has shed light on how this is achieved in every single cell, all of which maintain their own individual circadian oscillation. Here I will highlight the current understanding of how the major entraining cues of light, feeding and temperature are communicated to cells to alter their phase. Knowledge of the mechanisms of cellular entrainment has the capacity to impact both fundamental understanding of circadian rhythms and our application of cellular circadian research to real-world problems, including shift work.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 6","pages":"837-846"},"PeriodicalIF":3.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556607","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":"By dawn or dusk—how circadian timing rewrites bacterial infection outcomes","authors":"Devons Mo,&nbsp;Catherine S. Palmer,&nbsp;Jacqueline M. Kimmey","doi":"10.1002/1873-3468.70212","DOIUrl":"10.1002/1873-3468.70212","url":null,"abstract":"<p>The immune system exists in perpetual co-evolution with pathogens, and microbial pathogenesis is inexorably linked to the cyclical interactions between the pathogen and the host. Because pathogens exploit the immune system in unique ways, the antimicrobial efficacy of any given immune process varies between pathogens, and the consequences of activation or inhibition of antimicrobial programs must be interpreted in the context of the given pathogen. An increasing body of literature shows that numerous facets of the immune system are tightly regulated by the circadian clock, with multiple immune processes demonstrating increased activity during certain times of the day. However, the field of circadian immunology has generally given its attention to unraveling the mechanism of circadian regulation and comparatively little attention to how these circadian oscillations may influence the ultimate outcome of diseases. Therefore, this review aims to interpret these findings in the context of a select number of clinically relevant pathogens: <i>Salmonella enterica</i>, <i>Listeria monocytogenes</i>, and <i>Streptococcus pneumoniae</i>. In this way, we hope to discuss the complex factors that determine how the circadian clock regulates disease progression.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 6","pages":"864-893"},"PeriodicalIF":3.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471057","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":"It's about time—Circadian rhythms and the temporal control of biology","authors":"Carrie L. Partch","doi":"10.1002/1873-3468.70331","DOIUrl":"10.1002/1873-3468.70331","url":null,"abstract":"&lt;p&gt;Circadian rhythms coordinate biological timekeeping on a ~ 24-h timescale, aligning physiology and behavior with the daily solar cycle on Earth. The molecular clocks that generate circadian rhythms are found in both prokaryotes and eukaryotes, where they create oscillations in the abundance and/or activity of core clock proteins and clock-controlled genes that lead to temporal control of downstream processes from metabolism [&lt;span&gt;[1]&lt;/span&gt;] to immune function [&lt;span&gt;[2]&lt;/span&gt;] to cell division [&lt;span&gt;[3]&lt;/span&gt;]. This &lt;i&gt;FEBS Letters&lt;/i&gt; special issue on ‘Circadian clocks’ focuses on recent advances in our understanding of the molecular basis of circadian rhythms, their pervasive and powerful control of biology, and new frontiers in the field, including approaches to modulate biological timekeeping to improve human health.&lt;/p&gt;&lt;p&gt;The review article by Liu and Sancar highlights our current understanding of the mammalian circadian clock and its impact on human health [&lt;span&gt;[4]&lt;/span&gt;]. Based on genetic and biochemical studies, we now understand that the transcription/translation feedback loop (TTFL) that underlies mammalian circadian rhythms is initiated by the heterodimeric transcription factor, CLOCK:BMAL, and followed by two distinct steps of transcriptional repression mediated by other core clock components, such as the period (PER) and cryptochrome (CRY) proteins. The circadian clock directly impacts human health by influencing sleep patterns, metabolism, DNA repair and the cell cycle. Otobe and Yoshitane explain ‘in a nutshell’ how post-translational modification (PTM) of CLOCK and BMAL1 by phosphorylation regulates their activity, and describe open questions about the essential role that phosphorylation is known to play in regulating other clock components during the repressive phase of the molecular clock [&lt;span&gt;[5]&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In their review, Rao and Srivastava share a structural viewpoint on molecular circadian clocks, describing how insights into protein structure from cyanobacteria to humans have informed our understanding of clock mechanisms [&lt;span&gt;[6]&lt;/span&gt;]. They make a compelling argument that computational studies such as molecular simulations and structural modeling can be used to take us beyond current experimental limitations to bring new insight to clock protein function. Importantly, nearly all eukaryotic clock proteins have regions of extensive intrinsic disorder that are required for their function. By definition, these intrinsically disordered proteins (IDPs) lack tertiary structure—instead, they are highly dynamic in nature and often work in concert with structured domains to impart flexibility in clock protein regulation. The review by Usher and Pelham describes the interesting ensemble properties of IDPs and how they are frequently regulated by different PTMs to contribute to circadian timekeeping from humans to fungi [&lt;span&gt;[7]&lt;/span&gt;]. In their perspective, Larrondo et al. detail the structure and function o","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 6","pages":"713-715"},"PeriodicalIF":3.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://febs.onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520403","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":"Phosphorylation of CLOCK and BMAL1—a key regulatory mechanism in the mammalian circadian clockwork","authors":"Yuta Otobe,&nbsp;Hikari Yoshitane","doi":"10.1002/1873-3468.70194","DOIUrl":"10.1002/1873-3468.70194","url":null,"abstract":"<p>In the mammalian circadian clockwork, transcriptional-translational feedback loops are mediated by the core clock proteins, CLOCK and BMAL1. Although the transcriptional activation function of the CLOCK-BMAL1 complex has been well-characterized, the mechanisms underpinning its inactivation, particularly during the repression phase, which is mediated by PER and CRY proteins, remain incompletely understood. Recent studies have shed light on the critical role of phosphorylation within the DNA-binding domains of CLOCK and BMAL1 in modulating their DNA-binding activity and enabling PER-dependent repression. In this review, we summarize landmark studies that collectively delineate a phosphorylation-mediated “displacement” model for CLOCK-BMAL1 inactivation, explore its impact on circadian period regulation, and propose a molecular mechanism that links structural modulation with transcriptional timing.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 6","pages":"732-737"},"PeriodicalIF":3.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://febs.onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318302","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":"The elusive rhythms of bacterial life","authors":"Holly Kay,&nbsp;Maria Luísa Jabbur","doi":"10.1002/1873-3468.70287","DOIUrl":"10.1002/1873-3468.70287","url":null,"abstract":"<p>Circadian clocks are endogenous timekeeping mechanisms that are phylogenetically widespread. Despite the immense diversity of bacterial life, to date, clocks have been identified in few bacterial species. The cyanobacterial clock is understood in great detail, and the roles of its clock proteins in other types of timing mechanisms and in stress resistance are being studied in an ever-growing range of species. Studies of host-associated microbiomes have shown that host and microbial rhythmicity impact one another reciprocally. However, bacterial rhythms have primarily been studied in species in isolation or in host-associated microbiomes. Here, we summarize the state of the field of microbial chronobiology and propose the hypothesis that rhythmicity could be an emergent property of microbial interactions in free-living bacterial communities.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 6","pages":"980-994"},"PeriodicalIF":3.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://febs.onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003285","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}