FEBS Letters最新文献

{"title":"Ablation of LRP6 in alpha-smooth muscle actin-expressing cells abrogates lung inflammation and fibrosis upon bleomycin-induced lung injury.","authors":"Eun-Ah Sung, Mikhail G Dozmorov, SuJeong Song, Theingi Aung, Min Hee Park, Patricia J Sime, Wook-Jin Chae","doi":"10.1002/1873-3468.15106","DOIUrl":"10.1002/1873-3468.15106","url":null,"abstract":"<p><p>Tissue fibrosis is a progressive pathological process with excessive deposition of extracellular matrix proteins (ECM). Myofibroblasts, identified by alpha-smooth muscle actin (αSMA) expression, play an important role in tissue fibrosis by producing ECM. Here, we found that the Wnt antagonist Dickkopf1 (DKK1) induced gene expressions associated with inflammation and fibrosis in lung fibroblasts. We demonstrated that genetic deletion of LRP6, a receptor for Wnt ligands and DKK1, in αSMA-expressing cells using Acta2-cre Lrp6^fl/fl (Lrp6^AKO) mice abrogated the bleomycin (BLM)-induced lung inflammation and fibrosis phenotype, suggesting an important role for LRP6 in modulating inflammation and fibrotic processes in the lung. Our results highlight the crucial role of LRP6 in fibroblasts in regulating inflammation and fibrosis upon BLM-induced lung injury.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052115","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":"Transcription: friend or foe of genome stability","authors":"Emmanuel Compe,&nbsp;Donata Orioli","doi":"10.1002/1873-3468.15091","DOIUrl":"10.1002/1873-3468.15091","url":null,"abstract":"&lt;p&gt;Over the past 60 years, tremendous progress has been made in elucidating the highly regulated process of transcription, a cellular mechanism during which RNA polymerases copy specific DNA sequences into RNA. Initially considered as simple messengers between DNA and protein synthesis, it is now undeniable that RNA transcripts play fundamental roles in various aspects of DNA metabolism, ranging from gene expression regulation to chromatin remodelling [&lt;span&gt;[1, 2]&lt;/span&gt;]. Furthermore, a convergence of molecular and genomic evidence reveal that pre-existing RNA and &lt;i&gt;de novo&lt;/i&gt; RNA may directly or indirectly contribute to DNA damage signalling pathways and preservation of genome integrity [&lt;span&gt;[3]&lt;/span&gt;]. This is well-illustrated by the long noncoding &lt;i&gt;telomeric&lt;/i&gt; repeat-containing RNA (TERRA), which directly participates in genomic integrity by contributing to telomere maintenance [&lt;span&gt;[4-6]&lt;/span&gt;]. Besides the genome-protective function of RNAs, the transcriptional process itself is crucial for genome maintenance. By unwinding and scanning the DNA double helix, the transcription process contributes towards the identification and repair of a wide variety of DNA lesions. Indeed, impediments of transcription elongation caused by DNA lesions result in stalling of RNA polymerases, whose outcome can be detrimental to cell survival. The stalling of RNA polymerases can nevertheless promote the recruitment of DNA repair machineries to the damaged sites. Depending on the nature of the lesions, a wide variety of transcription-coupled repair mechanisms thus exist, which enable efficient repair of transcribed regions as well as fast restart of transcription after genotoxic stress [&lt;span&gt;[7-11]&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;However, transcription can also be a source of genomic instability. Indeed, it can directly induce DNA damage by generating torsional stress on the double helix structure or exposing single-strand DNA to genotoxic agents [&lt;span&gt;[12]&lt;/span&gt;]. In addition, a collision between transcription and other processes occurring on DNA, such as DNA replication, may have a nefarious outcome on genome integrity [&lt;span&gt;[13]&lt;/span&gt;]. Both transcription and DNA replication machineries are large multiprotein assemblies that cannot simultaneously stand on the same DNA strand. Their collision gives rise to conflicts that, if not properly resolved, may result in transcription and replication stalling as well as the generation of DNA double-strand breaks (DSBs) [&lt;span&gt;[13, 14]&lt;/span&gt;]. Furthermore, the unwinding of guanine (G)-rich DNA sequences during transcription may result in the formation of stable noncanonical DNA structures, such as G-quadruplexes (G4), which normally contribute to transcription as well as telomere maintenance, recombination and epigenetic regulation [&lt;span&gt;[15]&lt;/span&gt;]. However, depending on their localization or persistence, the G4 structures may induce genome instability by causing DNA breaks. Similarly, transcription of GC-rich DNA se","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 2","pages":"143-146"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.15091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045745","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":"Molecular insights into the modulation of the 5HT_2A receptor by serotonin, psilocin, and the G protein subunit Gqα.","authors":"Niklas Viohl, Ali Asghar Hakami Zanjani, Himanshu Khandelia","doi":"10.1002/1873-3468.15099","DOIUrl":"https://doi.org/10.1002/1873-3468.15099","url":null,"abstract":"<p><p>5HT_2AR is a G-protein-coupled receptor that drives many neuronal functions and is a target for psychedelic drugs. Understanding ligand interactions and conformational transitions is essential for developing effective pharmaceuticals, but mechanistic details of 5HT_2AR activation remain poorly understood. We utilized all-atom molecular dynamics simulations and free-energy calculations to investigate 5HT_2AR's conformational dynamics upon binding to serotonin and psilocin. We show that the active state of 5HT_2AR collapses to a closed state in the absence of Gqα, underscoring the importance of G-protein coupling. We discover an intermediate \"partially-open\" receptor conformation. Both ligands have higher binding affinities for the orthosteric than the extended binding pocket. These findings enhance our understanding of 5HT_2AR's activation and may aid in developing novel therapeutics. Impact statement This study sheds light on 5HT_2AR activation, revealing intermediate conformations and ligand dynamics. These insights could enhance drug development for neurological and psychiatric disorders, benefiting researchers and clinicians in pharmacology and neuroscience.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045744","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":"Interaction between bacterial phytochromes Agp1 and Agp2 of Agrobacterium fabrum by fluorescence resonance energy transfer and docking studies.","authors":"Afaf El Kurdi, Gero Kaeser, Patrick Scheerer, David Hoffmann, Ebru Akkus, Marcus Elstner, Norbert Krauß, Tilman Lamparter","doi":"10.1002/1873-3468.15102","DOIUrl":"https://doi.org/10.1002/1873-3468.15102","url":null,"abstract":"<p><p>Phytochromes are biliprotein photoreceptors found in bacteria, fungi, and plants. The soil bacterium Agrobacterium fabrum has two phytochromes, Agp1 and Agp2, which work together to control DNA transfer to plants and bacterial conjugation. Both phytochromes interact as homodimeric proteins. For fluorescence resonance energy transfer (FRET) measurements, various Agp1 mutants and wild-type Agp2 were labeled with specific fluorophores to study their interaction. FRET efficiencies rose from position 122 to 545 of Agp1. The photosensory chromophore module (PCM) of Agp1 did not show a FRET signal, but the PCM of Agp2 did. Docking models suggest that Agp1 and Agp2 interact with their histidine kinase and PCM perpendicular to each, around 45 amino acids of Agp1 or Agp2 are involved.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045527","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":"Elucidation of interface interactions between a dehydratase domain and an acyl carrier protein in cremimycin polyketide synthase.","authors":"Kaede Kotagiri, Haruka Tachibana, Daisuke Kawasaki, Taichi Chisuga, Toma Kashima, Shinya Fushinobu, Fumitaka Kudo, Tadashi Eguchi, Akimasa Miyanaga","doi":"10.1002/1873-3468.15103","DOIUrl":"https://doi.org/10.1002/1873-3468.15103","url":null,"abstract":"<p><p>Modular polyketide synthases (PKSs) are multi-domain enzymes involved in the biosynthesis of polyketide natural products. The dehydratase (DH) domain catalyzes the dehydration of the β-hydroxyacyl unit attached to the acyl carrier protein (ACP) domain in modular PKS. Although the DH domain likely recognizes the cognate ACP domain during the dehydration reaction, the molecular basis of DH-ACP interactions remains elusive. In this study, we conducted cross-linking analysis using a pantetheine-type probe for investigating the ACP recognition of a fusion-DH protein generated from a split-DH domain of cremimycin PKS. Based on the AlphaFold 3-predicted model structure of the fusion-DH-ACP complex, DH-ACP interface residues were identified and validated by mutational analysis. Our findings provide the first detailed insights into domain-domain interactions between DH and ACP in modular PKSs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045359","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":"Endothelial lipase-binding peptides similar to netrin-1 inhibit hepatitis B virus infection.","authors":"Mayuko Ide, Noriko Tabata, Kazuhisa Murai, Yuko Yonemura, Ying Wang, Atsuya Ishida, Takayoshi Shirasaki, Shuichi Kaneko, Satoru Ito, Masao Honda, Hiroshi Yanagawa","doi":"10.1002/1873-3468.15101","DOIUrl":"https://doi.org/10.1002/1873-3468.15101","url":null,"abstract":"<p><p>Hepatitis B virus (HBV) infects cells by attaching to heparan sulfate proteoglycans (HSPG) and Na⁺/taurocholate cotransporting polypeptide (NTCP). The endothelial lipase LIPG bridges HSPG and HBV, facilitating HBV attachment. From a randomized peptide expression library, we identified a short sequence binding to LIPG. This identified sequence closely resembled a sequence in the V domain of netrin-1, a protein known to bind heparin through its V domain. We designed two synthetic peptides based on this sequence and found that both synthetic peptides and netrin-1 suppressed HBV infection in chimeric mice with humanized livers and in primary hepatocytes isolated from them. The data reveal an antiviral function of the peptides and netrin-1 in HBV infection that is independent of LIPG lipase activity.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045526","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 histidine-rich extension of the mitochondrial F₀ subunit ATP6 from the ice worm Mesenchytraeus solifugus increases ATP synthase activity in bacteria.","authors":"Truman Dunkley, Daniel H Shain, Eric A Klein","doi":"10.1002/1873-3468.15100","DOIUrl":"https://doi.org/10.1002/1873-3468.15100","url":null,"abstract":"<p><p>Bioenergetic profiles of psychrophiles across domains of life are unusual in that intracellular ATP levels increase with declining temperature. Whole-transcriptome sequencing of the glacier ice worm Mesenchytraeus solifugus revealed a unique C-terminal extension on the ATP6 protein, which forms part of the proton pore of mitochondrial ATP synthase (Complex V). This extension, positioned near the proton exit pore, comprises alternating histidine residues thought to increase proton flux through Complex V leading to elevated ATP synthesis. To test this hypothesis, we fused the M. solifugus C-terminal extension to Escherichia coli AtpB (the ATP6 orthologue) and observed a ~ 5-fold increase in ATP synthesis. This enhancement was unidirectional as we observed no change to ATP hydrolysis rates. These findings offer an avenue for identifying critical factors associated with ice worm adaptation.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002648","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":"Diphthamide synthesis is linked to the eEF2-client chaperone machinery.","authors":"Lars Kaduhr, Klaus Mayer, Raffael Schaffrath, Johannes Buchner, Ulrich Brinkmann","doi":"10.1002/1873-3468.15095","DOIUrl":"https://doi.org/10.1002/1873-3468.15095","url":null,"abstract":"<p><p>The diphthamide modification of eukaryotic translation elongation factor (eEF2) is important for accurate protein synthesis. While the enzymes for diphthamide synthesis are known, coordination of eEF2 synthesis with the diphthamide modification to maintain only modified eEF2 is unknown. Physical and genetic interactions extracted from BioGRID show a connection between diphthamide synthesis enzymes and chaperones in yeast. This includes the Hsp90 co-chaperones Hgh1 and Cpr7. The respective co-chaperone deletion strains contained eEF2 without diphthamide. Notably, strains deficient in other co-chaperones showed no defect in the eEF2-diphthamide modification. Our results demonstrate that diphthamide synthesis involves not only Dph enzymes but also the eEF2-interacting co-chaperones Hgh1 and Cpr7 and may thus require a conformational state of eEF2 which is maintained by specific (co-)chaperones.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002652","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":"Characterization of fungal carbonyl sulfide hydrolase belonging to clade D β-carbonic anhydrase.","authors":"Ryuka Iizuka, Takahiro Ogawa, Rikako Tsukida, Keiichi Noguchi, David Hibbett, Yoko Katayama, Makoto Yoshida","doi":"10.1002/1873-3468.15098","DOIUrl":"https://doi.org/10.1002/1873-3468.15098","url":null,"abstract":"<p><p>Carbonyl sulfide hydrolase (COSase) is a unique enzyme that exhibits high activity towards carbonyl sulfide (COS) but low carbonic anhydrase (CA) activity, despite belonging to the CA family. COSase was initially identified in a sulfur-oxidizing bacterium and later discovered in the ascomycete Trichoderma harzianum strain THIF08. The COSase from T. harzianum has been recognized as a key enzyme in the assimilation of gaseous COS, and homologous genes are widely present not only in Ascomycota but also in Basidiomycota. Here, we characterized the COSases from the basidiomycete Gloeophyllum trabeum NBRC 6430 and T. harzianum to obtain detailed characteristics of fungal COSase. This study contributes to a better understanding of COS metabolism in fungi.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962146","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":"Calcium-sensing receptor- and ADAM10-mediated klotho shedding is regulated by tetraspanin 5.","authors":"Zhenan Liu, Joonho Yoon, Eunyoung Lee, Audrey N Chang, R Tyler Miller","doi":"10.1002/1873-3468.15078","DOIUrl":"https://doi.org/10.1002/1873-3468.15078","url":null,"abstract":"<p><p>Soluble, circulating Klotho (sKlotho) is essential for normal health and renal function. sKlotho is shed from the renal distal convoluted tubule (DCT), its primary source, via enzymatic cleavage. However, the physiologic mechanisms that control sKlotho production, trafficking, and shedding are not fully defined. We previously found that the G protein-coupled calcium-sensing receptor (CaSR) co-localizes with membrane-bound αKlotho and the disintegrin/metalloprotease ADAM10 in the DCT and controls sKlotho in response to CaSR ligands and pHo by activating ADAM10. Here, we advance understanding of this process by showing that tetraspanin 5 (Tspan5), a scaffolding and chaperone protein, contributes to the cell surface expression and specificity of a protein complex that includes Tspan5, ADAM10, Klotho, and CaSR. These results support a model of multiprotein complexes that confer signaling specificity beyond CaSR on G protein-coupled processes. Impact statement Systemic circulating sKlotho is a determinant for normal physiology. Studies of knockout animals established its role as an anti-aging protein. The regulatory mechanisms for Klotho production and secretion are largely unknown. We report that Tspan 5 contributes to CaSR- and ADAM10-dependent Klotho shedding from the kidney, its primary source.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946818","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}