The FEBS journal最新文献

{"title":"Ubiquitination dynamics in human tumour viruses: Viral infection, oncogenesis and antiviral therapy.","authors":"Oscar Trejo-Cerro, Martina Bergant Marušič, Justyna Broniarczyk","doi":"10.1111/febs.70224","DOIUrl":"https://doi.org/10.1111/febs.70224","url":null,"abstract":"<p><p>The ubiquitin conjugation system is a critical regulator of cellular homeostasis and influences various cellular processes. Viruses, as obligate intracellular parasites, have evolved sophisticated strategies to utilise this system to enhance their survival, to either increase virus production or ensure the long-term survival of the latently infected host. Viruses from almost all families, including RNA and DNA viruses, are challenged by ubiquitin-mediated mechanisms at different stages of their life cycle and have evolved to exploit or bypass the host cell ubiquitination system for their own replication. In this review, we examine the diverse functions of the ubiquitin conjugation system during the different stages of viral infection, including viral entry, replication, gene expression, assembly and release. We discuss how human oncogenic viruses manipulate host ubiquitination pathways to maintain infection, evade immune responses and drive oncogenesis. Finally, we highlight new research aimed at uncovering the precise molecular interactions between oncoviruses and the host ubiquitination system, which will pave the way for the development of advanced therapeutic strategies to treat viral infections and cancer.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862756","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":"Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.","authors":"Maria Poles, Raffaella Pacchiana, Chiara Mortali, Barbara Cisterna, Nidula Mullappilly, Adriana Celesia, Federica Danzi, Martina Gaspari, Daniela Cecconi, Massimo Donadelli, Alessandra Fiore","doi":"10.1111/febs.70223","DOIUrl":"https://doi.org/10.1111/febs.70223","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by poor prognosis and frequent gain-of-function mutations in the TP53 tumor suppressor gene. Given the crucial role of mutant p53 in the context of metabolic reprogramming and aggressive tumor behavior, we explored its role on mitochondria, which may present a valuable therapeutic target. In this study, we characterized the unique mitochondrial proteome observed in PDAC cells harboring the gain-of-function TP53^R273H mutation and discovered a strong mutant p53-dependent upregulation of myosin heavy chain 14 (MYH14), a nonmuscle myosin, implicated in mitochondrial dynamics. We deeply investigated the role of mutant p53 in the regulation of mitochondrial architecture and functionality in PDAC cells. Our morphological and morphometric analyses with transmission electron microscopy and three-dimensional confocal imaging revealed that mutant p53 induced marked mitochondrial fragmentation, whereas wild-type p53 stimulated mitochondrial elongation. Interestingly, the fragmented mitochondrial morphology is associated with higher mitochondrial respiration levels and more efficient mitochondrial cristae. These findings support the role of oncogenic mutant p53 isoforms in inducing mitochondrial fragmentation through a mechanism involving MYH14, resulting in an increased oxidative phosphorylation level that may support PDAC cell growth and aggressiveness.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862754","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":"Structural insights into disease mechanisms","authors":"Hajrah Khawaja,&nbsp;Julija Hmeljak","doi":"10.1111/febs.70226","DOIUrl":"10.1111/febs.70226","url":null,"abstract":"<p>Uncovering the mechanisms underlying disease remains a central focus of biomedical research. In this dedicated Focus Issue of <i>The FEBS Journal</i>, we are delighted to highlight some excellent interdisciplinary original research and Review articles that combine fundamental structural insight with mechanistic implications for disease. These articles demonstrate the importance of structural insights in uncovering disease mechanisms across a range of biological systems and point to the pivotal role of appropriate disease models for studying them. Together, they reinforce the perspective that structural information is essential for unravelling the mechanistic basis of disease and consequently guiding the development of therapeutic strategies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"292 18","pages":"4743-4746"},"PeriodicalIF":4.2,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and effective brightness of near-infrared fluorescent protein iRFP713/C15S/V254C complexed with phycocyanobilin.","authors":"Alina A Remeeva, Olesya V Stepanenko, Sergey A Silonov, Alexander S Kuzmin, Kirill V Kovalev, Olga V Stepanenko, Anastasia A Gavrilova, Eugene Y Smirnov, Irina M Kuznetsova, Konstantin K Turoverov, Ivan Y Gushchin, Alexander V Fonin","doi":"10.1111/febs.70220","DOIUrl":"https://doi.org/10.1111/febs.70220","url":null,"abstract":"<p><p>Tetrapyrrole-binding proteins are promising near-infrared fluorescent markers. We recently showed that the near-infrared fluorescent protein iRFP713, derived from bacteriophytochrome from Rhodopseudomonas palustris (RpBphP2), when mutated (iRFP713/C15S/V254C; hereafter referred to as iRFP) and complexed with phycocyanobilin (PCB) as a chromophore (iRFP-PCB), has a significantly higher fluorescence quantum yield than that of iRFP complexed with biliverdin (iRFP-BV). Here, we show that iRFP-PCB can be used as a fluorescent biomarker in eukaryotic cells (HEK293T) and that the effective brightness of iRFP-PCB is more than four times higher than that of iRFP-BV. We elucidated the structural basis of iRFP interaction with PCB by determining its crystal structure. Interestingly, we observed both parallel and antiparallel arrangements of iRFP protomers in an asymmetric unit cell. We used molecular dynamics simulations to show that the mobility of the protein and chromophore covalently bound to Cys254 is similar in different assembly states and in complexes with BV or PCB. Overall, the results indicate that PCB is a promising chromophore for the development of new fluorescent biomarkers from bacterial phytochromes and provide a basis for the further engineering of biomarkers from iRFP and related proteins.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839591","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":"Arv1 interacts with and regulates the first step of GPI biosynthesis in Candida albicans.","authors":"Monika Bharati, Harshita Saini, Neha Thakran, Yatin Kumar, Shailja Shefali, Usha Yadav, Sunyna Saun, Aaisha Anzar, Sneha Sudha Komath","doi":"10.1111/febs.70217","DOIUrl":"https://doi.org/10.1111/febs.70217","url":null,"abstract":"<p><p>The ubiquitous ARV1 gene shows significant functional conservation across eukaryotes. Saccharomyces cerevisiae Arv1 is implicated in several cellular processes, including lipid/sterol homeostasis, morphogenesis, and drug resistance. Human and fungal ARV1 functionally complement S. cerevisiae ARV1, and arv1Δ is rescued by the overexpression of some subunits of the GPI-N-acetylglucosaminyltransferase (GPI-GnT), which catalyzes the first GPI biosynthetic step. Human and Trypanosoma brucei Arv1 homologs co-immunoprecipitate with different GPI-GnT subunits. Based on these previous reports, we hypothesized a cross talk between Candida albicans ARV1 and the first step of GPI biosynthesis. Using super-resolution radial fluctuation (SRRF) analysis of co-localization data, co-immunoprecipitation assays, and acceptor-photobleaching FRET studies, we show that CaArv1 physically interacts with the GPI-GnT. It also regulates the expression of the GPI-GnT subunits via the epigenetic modulator, Rtt109. Overexpressing GPI19 (which encodes a GPI-GnT subunit whose expression is repressed in Caarv1Δ/Δ) rescues its cell wall phenotype, sensitivity to azoles, and GPI-GnT activity without reversing the filamentation defect. A similar rescue is observed on downregulating GPI2 (encoding another GPI-GnT subunit, whose expression is upregulated in Caarv1Δ/Δ). Thus, transcriptional control rather than physical interaction appears to be the primary mechanism by which CaArv1 controls GPI-GnT. Overexpressing RAS1 restores all phenotypes, including filamentation, without restoring GPI-GnT activity. The filamentation defect of Caarv1Δ/Δ is independent of the GPI-GnT. CaArv1 transcriptionally regulates hyphae-specific transcription factors downstream of cAMP-PKA signaling (Efg1, Flo8) and repressors (Tup1, Nrg1) to modulate filamentation. The cross talk between CaArv1 and GPI-GnT has important implications for the virulence of C. albicans.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839589","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":"Ageing versus developmental silencing: Answers from the epigenome.","authors":"Kirsten C Sadler, Mekayla A Storer, N Sumru Bayin","doi":"10.1111/febs.70221","DOIUrl":"https://doi.org/10.1111/febs.70221","url":null,"abstract":"<p><p>A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition from the developmental processes of embryogenesis through maturation to adulthood, as well as the processes that occur as an animal reaches the end of its lifespan. In some cases, the loss of regenerative capacity occurs once development is complete, and in others it occurs in the latter part of the animal's life. Regardless, the loss of regenerative capacity is caused by a failure to activate genes required for successful regeneration. This, in part, can be attributed to restructuring of the epigenome.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839588","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":"N-terminal helix formation and dimer-monomer transition of FGF10 in specific recognition of FGFR2b.","authors":"Hyunjae Park, Yoon Sik Park, Kiwoong Kwak, Jiwon Yun, Hyeonmin Lee, Chae-Eun Lee, DongHyun Lee, Kyeong Won Lee, Young Jun An, Hyung-Soon Yim, Jung-Hyun Lee, Sun-Shin Cha, Lin-Woo Kang","doi":"10.1111/febs.70218","DOIUrl":"https://doi.org/10.1111/febs.70218","url":null,"abstract":"<p><p>Fibroblast growth factors (FGFs) are crucial for various cellular functions, including proliferation, differentiation, tissue repair, and immune responses. FGF10, part of the FGF7 subfamily, binds to the FGFR2b receptor via heparin sulfate. We determined the crystal structure of human FGF10 alone. In the FGFR2b-bound form, the N-terminal region of FGF10 formed an α1 helix. This α1 helix, however, exists as a flexible loop with dual conformations in the unbound structure. Deleting this conformationally dynamic α1 helix reduces cell proliferation activity in vitro. Receptor-binding-induced formation of the α1 helix in FGF10 creates a distinct protruded knob and concave pocket on the globular core of FGFs, increasing the FGFR2b-binding surface by 37%. Size-exclusion chromatography showed a concentration-dependent dimer-monomer shift in purified FGF10, with the hydrophobic dimer interface aligning with the FGFR2b D2-domain-binding surface. These findings suggest that the conformational change in the N-terminal region and the dimer-monomer shift are critical for FGF10's specific binding to FGFR2b, highlighting the functional significance of these structural adaptations.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839590","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":"A patient-derived orthotopic xenograft model unveils metastatic dynamics in head and neck squamous cell carcinoma.","authors":"Yuchen Bai, Benjamin Blyth, Jarryd Boath, Qiji Deng, Ruihong Huang, Charbel Darido","doi":"10.1111/febs.70216","DOIUrl":"https://doi.org/10.1111/febs.70216","url":null,"abstract":"<p><p>Metastasis presents a significant challenge in head and neck squamous cell carcinoma (HNSC), profoundly impacting patient morbidity and mortality. This proof-of-concept study establishes patient-derived orthotopic xenografts (PDOXs) as an advanced preclinical model to investigate and address metastatic HNSC. Indeed, PDOXs demonstrate noteworthy histopathological and molecular fidelity to primary HNSC tumours. Contrary to the traditional subcutaneous xenografts, PDOXs authentically replicate local lymph node metastasis, mirroring the intricate site-specific cancer-stroma interaction and the disease progression in patients. Furthermore, genomic and transcriptomic analyses underscore the genetic accuracy and heightened resemblance of PDOXs to patient tumours. Notably, nuclear factor kappa-B (NF-κB)-signalling-induced inflammation emerges as a key driver of the metastatic process, unveiling an inflammatory signature with potential implications as a prognostic marker and therapeutic target. These findings underscore the pivotal role of the PDOX model in capturing the complex biology of HNSC, providing insights for precision-targeted therapies and enhancing patient outcomes.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823490","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":"Characterization of the carboxy-terminal domain of the GPN-loop GTPase Npa3 reveals an intrinsically disordered region and phosphorylation-dependent regulation in the absence of BUD27.","authors":"Manuel de Jesús Ochoa-Valdez, Martín Mora-García, Edgar D Páez-Pérez, Beatriz E González-Contreras, Yolanda Rebolloso-Gómez, Lina R Riego-Ruiz, Mónica R Calera, Roberto Sánchez-Olea","doi":"10.1111/febs.70214","DOIUrl":"https://doi.org/10.1111/febs.70214","url":null,"abstract":"<p><p>Yeast GPN-loop GTPase 1 (Npa3) is a member of the GPN-loop GTPase family involved in RNA polymerase II (RNAPII) assembly and nuclear targeting. Npa3 features a GTPase core and an enlarged carboxy-terminal domain (CTD) that is conserved in all eukaryotic orthologs but absent from the archaeal Gpn protein. We previously showed that Npa3 possesses additional cellular functions unrelated to RNAPII nuclear targeting. Although this enzyme was nuclear in cells expressing a truncated version of NPA3 lacking the last 106 residues (npa3∆C), these cells exhibited an increased sensitivity to the translation inhibitors hygromycin B and geneticin. Additionally, npa3∆C displayed a strong negative interaction with the bud site selection 27 deletion mutant (bud27∆). Despite the functional importance of the Npa3 CTD, little is known about its structure and regulation. Here, we show that the CTDs of Npa3 and its human ortholog GPN1 are predicted as intrinsically disordered regions (IDRs) containing three molecular recognition features (MoRFs). Both CTDs are disordered and acidic but differ widely in their primary sequences. Interestingly, Npa3 CTD function could be partially replaced by human GPN1 CTD. In proteomic studies, Npa3 was reported to be phosphorylated mainly at its CTD, but its physiological relevance remains unknown. In a bud27∆ background, strains expressing exclusively full-length, non-phosphorylatable Npa3, with eight CTD residues reported to be phosphorylated, mutated to alanine, displayed markedly increased sensitivity to hygromycin B and cycloheximide. The same phenotype was observed after simultaneously mutating only Ser304, Ser308, and Ser313 to alanine. We conclude that the Npa3 GTPase domain function is critically regulated by its disordered CTD through phosphorylation of the Ser304/Ser308/Ser313 cluster.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823491","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":"Defining the interactome of the pancreas-specific SPCA2 isoform (SPCA2C) identifies unique links to store-operated Ca²⁺ entry.","authors":"Petra Samardzija, Melissa A Fenech, Oneeb Hassan, Ryann Lang, McKenzie C Carter, Stephanie Chen, Selina Shi, Rithwik Ramachandran, Peter B Stathopulos, Christopher L Pin","doi":"10.1111/febs.70213","DOIUrl":"https://doi.org/10.1111/febs.70213","url":null,"abstract":"<p><p>Calcium (Ca²⁺) is critical for normal cell function, and several protein networks are required for Ca²⁺ signaling. In the pancreas, regulated changes in cytosolic Ca²⁺ allow for the exocytosis of zymogen granules, and altered Ca²⁺ signaling underlies pancreatic pathologies. Previously, our laboratory showed a pancreas-specific isoform of secretory pathway Ca²⁺-ATPase 2 (also known as calcium-transporting ATPase type 2C member 2; SPCA2), termed SPCA2C (gene name Atp2c2c, C-terminally truncated form), affects multiple pathways involved in Ca²⁺ homeostasis. The goal of this study was to define the SPCA2C interactome that contributes to these processes. Using proximity-dependent biotin identification, BioID, we expressed SPCA2C-BirA*^HA in HEK293 cells with constitutive calcium release-activated calcium channel protein 1 (Orai1) expression. A total of 150 high-confidence interacting proteins for SPCA2C were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analyses supported the localization of SPCA2C to the endoplasmic reticulum, and that it functions in Ca²⁺ signaling and vesicular transport. Stromal interaction molecule 1 (STIM1) and coiled-coil domain-containing protein 47 (CCDC47; also known as PAT complex subunit CCDC47) were among several proteins we confirmed as strong interactors through co-immunoprecipitation (co-IP). Co-expression of Atp2c2c and CCDC47 in HEK-Orai1^YFP cells increased store-operated calcium entry (SOCE) and resting cytosolic Ca²⁺ levels compared with the expression of either protein alone. We further teased out the domain determinants of CCDC47 interactions with SPCA2C, STIM1, and Orai1 using co-IP and co-localization experiments. CCDC47 localized with SPCA2C and the key store-operated Ca²⁺ entry mediators STIM1 and Orai1 but did not interact with the long SPCA2 isoform. These interactions were dependent on the presence of the CCDC47 coiled-coil or accessible transmembrane domains. Overall, we define several previously unknown protein interactions for SPCA2C, and suggest that CCDC47 may be involved in the coiled-coil interplay that underlies STIM1 and Orai1-mediated Ca²⁺ entry.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812821","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}