The FEBS journal最新文献

{"title":"Proteolytic remodelling of the extracellular matrix by pericytes.","authors":"Tina Burkhard, Ella Milne, Kate Qian, Paola Campagnolo, Salvatore Santamaria","doi":"10.1111/febs.70569","DOIUrl":"https://doi.org/10.1111/febs.70569","url":null,"abstract":"<p><p>Pericytes (PCs) are perivascular cells that lie in close association with endothelial cells (ECs), with both cell types embedded within a shared basement membrane (BM), a specialised form of extracellular matrix (ECM). PCs regulate vascular integrity, angiogenesis and capillary blood flow and are capable of differentiating into other cell types including fibroblasts and smooth muscle cells. In recent years, a central role for PCs in regulating the development and maturation of the vasculature, maintaining tissue homeostasis and directing the pleiotropic remodelling of tissues during regeneration has emerged. Here, we review how PCs contribute to the synthesis and remodelling of the ECM in different pathophysiological conditions. Moreover, we provide an atlas of the PC matrisome, the complex of ECM molecules expressed by PCs, based on recent transcriptomics (in particular single-cell RNA sequencing) and proteomics datasets, with the caveat that such an entity does not exist in isolation due to the physical and paracrine interactions between PCs, ECs and other cell types. Understanding the role of PCs in modulating their microenvironment through active synthesis and degradation of specific matrisome components is essential to understand the role these plastic cells play in angiogenesis and in different pathologic conditions, including stroke, Alzheimer's disease and cancer.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACTR3 enhances the hyperproliferation of psoriatic keratinocytes by activating the TAK1-MK2-HSP27 pathway.","authors":"Jianxiao Xing, Junqin Li, Ying Wang, Yanyang Liang, Yuanjun Yao, Yali He, Xuping Niu, Kaiming Zhang","doi":"10.1111/febs.70558","DOIUrl":"https://doi.org/10.1111/febs.70558","url":null,"abstract":"<p><p>Psoriasis is a chronic immune-mediated skin disorder characterised by abnormal keratinocyte proliferation and cutaneous inflammation. ACTR3 (actin-associated protein 3) is significantly overexpressed in both cutaneous malignant tumours and psoriatic keratinocytes, and is recognised as a potential key nodal molecule linking tumours to inflammatory skin conditions. Lysine 2-hydroxyisobutyrylation (Khib)-a critical post-translational modification-exerts regulatory effects on the pathogenesis of various diseases; however, its specific role in psoriasis pathogenesis remains elusive. In this study, we demonstrated that elevated ACTR3 expression in cutaneous tumours and psoriasis promotes abnormal keratinocyte proliferation in psoriasis. Khib-modified protein profiles in epidermal tissues from psoriatic patients and healthy controls were analysed, leading to the identification of ACTR3 as a differential target protein. Results showed that Khib modification levels at the K42 site of ACTR3 were significantly reduced in lesional tissues from psoriatic patients and imiquimod (IMQ)-induced psoriatic mice. Further validation using ACTR3 K42A mutation experiments confirmed that decreased Khib modification at this site exacerbates IMQ-induced psoriatic inflammation and keratinocyte proliferation. Deacetylases Sirt1 and HDAC1 were found to reduce ACTR3 Khib modification levels, thereby regulating ACTR3 expression and subsequent keratinocyte (KC) proliferation. Additionally, signalling pathway analysis revealed that downregulated K42-Khib modification of ACTR3 enhances keratinocyte proliferation by activating the TAK1-MK2-HSP27 pathway. Notably, TAK1 antagonists effectively reversed abnormal keratinocyte proliferation and psoriatic inflammation induced by the ACTR3 K42A mutation. This study elucidates that reduced Khib modification at the ACTR3 K42 locus promotes keratinocyte proliferation via regulation of the TAK1-MK2-HSP27 signalling pathway, offering a previously undescribed molecular insight into psoriasis pathogenesis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The different roles of the eS31 ribosomal protein in ribosome biogenesis and translation in Saccharomyces cerevisiae.","authors":"Eduardo Villalobo, Jesús de la Cruz","doi":"10.1111/febs.70580","DOIUrl":"https://doi.org/10.1111/febs.70580","url":null,"abstract":"<p><p>Many ribosomal proteins in yeast possess extensions that protrude from their globular cores to facilitate rRNA folding, ribosome assembly, and translation. Previous work established that the eukaryote-specific N-terminal domain of eS31 harbors a nuclear localization signal; its deletion impairs growth and 40S biogenesis while inducing ribosomal misreading. Gao et al., now provide further insights into this extension, identifying a critical cluster of basic residues essential for elongation fidelity. Furthermore, they demonstrate that full-domain deletion compromises termination through a 'trans-acting disruption' process requiring wild-type eS31. These findings highlight novel mechanisms underlying ribosome heterogeneity and specialization. Comment on: https://doi.org/10.1111/febs.70510.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential.","authors":"Dongyu Shu, Chalv Fu, Zhijun Liu, Chuanzhou Li","doi":"10.1111/febs.70574","DOIUrl":"https://doi.org/10.1111/febs.70574","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a progressive neurodegenerative disorder with a rising global prevalence, is pathologically characterised by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). These lesions lead to synaptic damage, neuronal loss, and cognitive impairment. Despite the recent approval of immunotherapies for AD treatment, their limited efficacy highlights the urgent need for exploring novel disease mechanisms and developing targeted therapeutic strategies. Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, participates in diverse physiological processes (e.g. membrane organisation, cytoskeleton linkage) and contributes to the pathogenesis of diseases such as cancer and Parkinson's disease. Emerging evidence indicates that ANXA2 interacts with AD-related pathological components (Aβ, tau) and regulates AD-associated inflammatory pathways, suggesting its potential role in AD. However, current evidence regarding ANXA2 in AD remains limited, and the molecular mechanisms underlying its contribution to AD pathogenesis remain unclear. This review comprehensively summarises the current knowledge on ANXA2's cellular and physiological functions in the central nervous system (CNS), as well as its involvement in AD pathology, aiming to provide guidance for research into ANXA2's therapeutic potential for AD prevention and treatment.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the active site cover of coproheme decarboxylase from Listeria monocytogenes.","authors":"Nikolaus Falb, Dominik Hörtnagel, Chris Oostenbrink, Paul G Furtmüller, Stefan Hofbauer","doi":"10.1111/febs.70575","DOIUrl":"https://doi.org/10.1111/febs.70575","url":null,"abstract":"<p><p>Coproheme decarboxylase (ChdC) is the terminal enzyme in Gram-positive heme b biosynthesis, an enzyme holding a special importance given its unique structure-function relationship and its necessity for bacterial survival. In the past, the enzyme has been shown to perform a double decarboxylation of two propionate groups on coproheme (Fe(III)-coproporphyrin III), subsequently converting it to heme b (iron-protoporphyrin IX). Notably, the active site of ChdCs is universally covered by a flexible loop. Its importance has not been fully studied but given its position it is assumed to provide steric hinderance for substrates or potential inhibitors to pass. This study aims to investigate its physiological role by introducing a histidine-to-alanine mutation located on the loop of ChdC from Listeria monocytogenes. Molecular dynamics simulation shows an increased flexibility of the structural element in the mutant. As a consequence, various kinetic studies at steady- and presteady-state conditions suggest coproheme binding and active site accessibility are improved. Using simulations and X-ray crystallography, we show evidence that the loop is originally stabilized by a hydrogen bond between S116 and the mutated H117. The higher accessibility also results in a higher susceptibility to damage from oxidative cosubstrates like H₂O₂, suggesting the loop in its wild-type conformation plays a key biological role in regulating the transfer of cosubstrates towards the main substrate coproheme.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PEG400 regulates Falcipain 2 activity through an allosteric mechanism.","authors":"Bikram Nath, Subhoja Chakraborty, Sampa Biswas","doi":"10.1111/febs.70546","DOIUrl":"https://doi.org/10.1111/febs.70546","url":null,"abstract":"<p><p>The malarial parasite Plasmodium falciparum cleaves to host haemoglobin through a cascade of proteolytic enzymes. The cysteine protease, Falcipain-2 (FP2), plays an essential role in the process and is important for parasite survival, making it a potential drug target. However, similarities with host cysteine cathepsins hamper selective inhibition, thus necessitating detailed structural and functional characterisations of FP2. This study uncovers a new regulatory role for polyethylene glycol 400 (PEG400) on FP2 activity. PEG400 inhibits FP2 activity on small peptide substrates and azo-casein, while enhancing haemoglobin degradation, exerting a dual effect on FP2 catalysis. Mixed-type inhibition has been observed for PEG400 against small peptide substrates of FP2. This is consistent with the binding of PEG400 to the catalytic cleft, confirmed by fluorescence quenching and docking studies. Unlike typical nonspecific PEG-protein interactions, PEG400 adopts a fit within the catalytic region of FP2 and partially overlaps with leupeptin-binding sites, albeit with a lower affinity. Computational analysis further identifies a previously undescribed allosteric binding pocket of PEG400, which is further supported by in silico mutagenesis and molecular dynamics simulation studies. This pocket exhibits minimal conservation in human cathepsins, suggesting its selective potential. In contrast to this inhibitory role, biochemical assays revealed that PEG400 promotes haemoglobin proteolysis. Spectroscopic analyses further suggest that PEG400 alters haemoglobin structural dynamics to favour proteolysis. Interestingly, ENM-based normal mode analysis revealed that upon haemoglobin binding, PEG400 restricts the FP2 hinge-bending motion, improves FP2-haemoglobin proximity, and PEG400 is simultaneously dislodged from the active site, thereby promoting proteolysis. Altogether, these results reveal a previously undescribed mechanism of FP2 regulation, highlighting new therapeutic avenues.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical stiffness orchestrates distinct regulation of MRTFs and YAP/TAZ transcriptional cofactors in hepatocytes.","authors":"Brenda Selene Torres-Ortiz, Daniel Pérez-Calixto, Jorge Carretero-Ortega, Aida Gabriela Guzman-López, Diana Cristina Pinto-Dueñas, Mariana Hernández-Juárez, Alejandra Jiménez-Escobar, Adriana Rodríguez-Hernández, Beatriz Díaz-Bello, Nathalia Serna-Márquez, Miguel Ángel Peña-Rico, Laura Gómez-Romero, Francisco Gabriel Vázquez-Cuevas, Genaro Vázquez-Victorio","doi":"10.1111/febs.70570","DOIUrl":"https://doi.org/10.1111/febs.70570","url":null,"abstract":"<p><p>During liver fibrosis, hepatocytes respond to progressive increases in tissue stiffness by undergoing cytoskeletal reorganisation. This has important consequences such as immune cell infiltration, mainly triggered by the activation of YAP and TAZ proteins. However, other proteins that respond to mechanical modifications remain poorly characterised; in particular, the myocardin-related transcription factors A and B (MRTFs). Here, we referred to these four proteins as mechanical responsive transcriptional cofactors (MRTcoF). We analysed the regulation of MRTcoF proteins in fibrotic livers induced by carbon tetrachloride (CCl₄) and observed that MRTcoF were differentially regulated during liver fibrosis, predominantly in hepatocytes. Transcriptome analysis suggested that fatty acid and glucose metabolisms, cell proliferation and signalling pathways were regulated by transcriptional enhanced associate domain (TEAD)- and serum response factor (SRF)-transcriptional programmes in CCl₄-treated livers. Then, we evaluated the protein expression levels of MRTcoF in primary hepatocytes (PH) cultured on tissue culture petri dishes (TCPD). After culture, we observed upregulation of MRTcoF, and downregulation of TAZ after protein increase. Interestingly, despite the increase in MRTFB protein levels, no accumulation of MRTFB was detected in the nucleus. Culture on soft polyacrylamide hydrogels (PAA HGs) attenuated the activation of MRTcoF, having specific implications in the transcriptional regulation of target genes. In contrast, pharmacological inhibition of MRTcoF was not sufficient to halt transcriptional regulation. In summary, a progressive increase of stiffness activates MRTcoF transcriptional complexes in hepatocytes, suggesting a key role of mechano-transduction during liver fibrosis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ICAM-1 mediated inhibition of microglial inflammation through ERK/STAT3 signalling pathway improves cognitive functions in 5xFAD mouse model of Alzheimer's disease.","authors":"Soumita Goswami, Nimai Gorai, Subhas Chandra Biswas","doi":"10.1111/febs.70531","DOIUrl":"https://doi.org/10.1111/febs.70531","url":null,"abstract":"<p><p>Microgliosis is one of the early hallmarks of Alzheimer's disease (AD) that plays a crucial role in disease pathogenesis. Microglia play a defensive role by phagocytosing and clearing amyloid-β (Aβ) aggregates. However, excessive uptake of Aβ leads to impairment of its clearing ability, which results in neuroinflammation and eventually neurodegeneration. Thus, enhancing microglial phagocytosis and reducing its pro-inflammatory functions are promising strategies for AD therapy. However, harnessing microglial activation for long-term benefits in controlling disease pathogenesis in AD is currently lacking. Our recent findings revealed that the astrocyte secreted cytokine Intercellular adhesion molecule 1 (ICAM-1) improves memory and cognitive impairments in a 5xFAD mouse model of AD. Here, we investigated the involvement of microglia in ICAM-1 function since its receptor, LFA-1, is expressed in microglia. We found that ICAM-1 blocks Aβ-mediated microglial inflammatory activation by inhibiting the ERK-STAT3 pathway, which is indispensable for microglial inflammation. Further, we found that ICAM-1 potentiates microglial phagocytic ability to eliminate Aβ in primary culture. Additionally, ICAM-1 reduced Aβ plaque load and associated microglial reactivation in the 5xFAD mouse hippocampus. This reduction in plaque-associated microgliosis led to improved synaptic protein expressions which was reflected in significant cognitive improvement. Moreover, blocking the binding between ICAM-1 with its receptor LFA-1 partially reduced ICAM-1-mediated microglial modification. Collectively, these findings suggest that ICAM-1 plays a pivotal role in modifying microglial phagocytic and inflammatory functions via the ERK-STAT3 signalling pathway, thereby contributing to Aβ clearance and cognitive improvements.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK14 is a critical regulator of haematopoietic stem and progenitor cell maintenance and post-transplantation proliferation.","authors":"Ya-Fei Li, Tian-Jing Li, Yin Huang, Ke Bai, Rong-Rong Gao, Jia-Xin Yang, Lan-Yue Ma, Yan-Mei Yu, Jinjin Ma, Qi Chen, Yang Liu","doi":"10.1111/febs.70562","DOIUrl":"https://doi.org/10.1111/febs.70562","url":null,"abstract":"<p><p>Cyclin-dependent kinase (CDK) 14 is involved in Wnt signalling, tissue repair, and tumourigenesis, but its function in haematopoiesis remains unexplored. Here, we found that CDK14 was necessary to maintain physiological haematopoiesis under steady-state and haematopoietic reconstitution after transplantation using genetic and pharmacological interventions. By utilising Cdk14 knockout and haematopoietic-deletion (Cdk14^∆HC) mouse models, in combination with the selective CDK14 inhibitor FMF-04-159-2, we showed that ablation of CDK14 resulted in diminished haematopoietic stem and progenitor cells (HSPCs), and disrupted the proportion of mature haematopoietic cells. Single-cell RNA sequencing analysis of bone marrow from Cdk14^∆HC mice revealed impaired cell cycle progression, perturbed HSPC proportion, and altered niche-HSPC interactions. Furthermore, genetic and pharmacological ablation of CDK14 markedly decreased HSPC proliferation after transplantation in vivo and reduced colony formation in vitro. These findings identify CDK14 as a critical regulator of haematopoietic homeostasis and highlight its essential role in supporting HSPC function under stress conditions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arsenite methyltransferase 3 is required for mitochondrial function and hepatic lipid metabolism.","authors":"Patrice Delaney, James Griffin, Nouf Khan, Balnur Ibrash, Matthew J O'Connor, Tomas Venit, Elizabeth Mayela Ambrosio, Spiros A Pergantis, Elke Ober, Piergiorgio Percipalle, Kirsten C Sadler","doi":"10.1111/febs.70559","DOIUrl":"https://doi.org/10.1111/febs.70559","url":null,"abstract":"<p><p>Arsenic poisoning has severe health effects, and accordingly, most research on the arsenite methyltransferase 3 (AS3MT) enzyme has focused on its role in arsenic metabolism, overlooking potential endogenous functions. We discovered an arsenic-independent role for AS3MT in regulating hepatic energy metabolism. as3mt loss in zebrafish caused differential expression of thousands of genes in the liver, with many of the downregulated genes playing roles in mitochondrial energy metabolism. Similar genes were downregulated in AS3MT-depleted human cells. as3mt zebrafish mutants had large, malformed mitochondria, were more sensitive to both arsenic and the mitochondrial toxin rotenone, and impaired swimming velocity. as3mt mutants developed steatosis, a hallmark of mitochondrial dysfunction. Restoring As3mt in hepatocytes of as3mt mutants rescued steatosis and mitochondrial gene expression. Overexpression of As3mt in wild-type hepatocytes protected against steatosis caused by iAs induced. This demonstrates a novel, conserved, endogenous role for As3mt in hepatic energy metabolism, identifies As3mt loss as a previously unrecognized cause of steatosis, and suggests that arsenic may induce mitochondrial dysfunction due to sequestering As3mt from its endogenous role.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}