Proceedings of the National Academy of Sciences of the United States of America最新文献

{"title":"Correction for Zhao et al., Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus.","authors":"","doi":"10.1073/pnas.2525323122","DOIUrl":"https://doi.org/10.1073/pnas.2525323122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"28 1","pages":"e2525323122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering cargo clients and accessory factors of AP-1 and AP-4 through vesicle proteomics","authors":"Ziqing Peng, Jingran Fan, Yang Liu, Qinyu Jia, Junkun An, Jianying Wang, Yan Huang, Zhong-Ping Yao, Yusong Guo","doi":"10.1073/pnas.2508961122","DOIUrl":"https://doi.org/10.1073/pnas.2508961122","url":null,"abstract":"The <jats:italic toggle=\"yes\">trans</jats:italic> -Golgi network (TGN) is a crucial sorting station in the secretory pathway, where adaptor protein (AP) complexes ensure selective cargo packaging into transport vesicles. However, the complete repertoire of cargoes and regulators associated with individual AP complexes remains poorly defined. Intriguingly, AP-4-mediated TGN export operates independently of clathrin, suggesting the involvement of uncharacterized accessory factors in vesicle biogenesis. To address these gaps, we developed an in vitro vesicle formation assay using wild-type HeLa cells or cells deficient in AP1γ1 or AP4ε, reconstituting their roles in packaging their known clients, Vangl2 and ATG9A, respectively. Coupling this assay with label-free quantitative mass spectrometry, we mapped distinct cargo profiles for AP-1 (which buds from the TGN and ARF1-positive endosomes) and AP-4, identifying the 45 kDa calcium-binding protein (CAB45) as an AP-1-dependent cargo and the Type-1 angiotensin II receptor-associated protein (ATRAP) as an AP-4-dependent cargo. Additionally, we uncovered PRRC1 and WDR44 as cytosolic regulators essential for AP-4-mediated TGN export. Our study advances the mechanistic understanding of AP-1 and AP-4 in secretory trafficking and provides a robust strategy to systematically identify cargo clients and accessory factors for specific adaptor complexes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"99 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for Hoffmann et al., Cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse.","authors":"","doi":"10.1073/pnas.2524777122","DOIUrl":"https://doi.org/10.1073/pnas.2524777122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"4 1","pages":"e2524777122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular basis of SARS-CoV-2 proofreading enzyme–mediated resistance to remdesivir","authors":"Yang Yang, Yu Li, Scott T. Becker, Ayesha Khan, Gloria Luo, Bin Liu, Chang Liu","doi":"10.1073/pnas.2519755122","DOIUrl":"https://doi.org/10.1073/pnas.2519755122","url":null,"abstract":"SARS-CoV-2’s remarkable resistance to nucleotide analog antivirals such as remdesivir, which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies. We reveal that remdesivir incorporation destabilizes RdRp–RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses. These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"96 2 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Operation Warp Speed offers a roadmap for improving the efficiency of bench to bedside medical advances.","authors":"Lawrence Corey","doi":"10.1073/pnas.2502975122","DOIUrl":"https://doi.org/10.1073/pnas.2502975122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"76 1","pages":"e2502975122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current progress and research needs to protect children's environmental health.","authors":"Katherine L O'Shaughnessy,Alyson N Lorenz,Elizabeth O Owens,Gregory G Miller,Daniel A Malashock,Laura M Carlson,Jill A Franzosa,Michael Wilson,Elizabeth B Boyle","doi":"10.1073/pnas.2522786122","DOIUrl":"https://doi.org/10.1073/pnas.2522786122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"2 1","pages":"e2522786122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional diversity in GII.4 norovirus entry: HBGA binding and capsid clustering dynamics","authors":"B. Vijayalakshmi Ayyar, Carmen V. Apostol, Janam Jitendra Dave, Soni Kaundal, Joseph A. Kendra, Frederick H. Neill, Khalil Ettayebi, Sarah Maher, Ramakrishnan Anish, Gabriel I. Parra, Göran Larson, Robert L. Atmar, Sue E. Crawford, B. V. Venkataram Prasad, Mary K. Estes","doi":"10.1073/pnas.2517493122","DOIUrl":"https://doi.org/10.1073/pnas.2517493122","url":null,"abstract":"Human noroviruses (HuNoVs), especially GII.4 strains, are the leading cause of acute viral gastroenteritis worldwide, yet no approved vaccines or antivirals exist. The pandemic GII.4 Sydney 2012 strain enters cells via membrane wounding and clathrin-independent carrier-mediated endocytosis, but it is unclear whether this entry mechanism is conserved across GII.4 variants. We compared early binding and entry of multiple GII.4 variants using wild-type and mutant GII.4 virus-like particles (VLPs) and modified human intestinal enteroid cultures. Only a subset of GII.4 variants, including GII.4 Sydney, form distinct, histo-blood group antigen (HBGA)-dependent capsid clusters on the cell surface. Clustering strains display significantly enhanced membrane wounding and endocytosis compared to nonclustering strains and outcompete nonclustering strains in replication assays exhibited by complete inhibition of GII.4 Sydney replication. Using mutant VLPs and an HBGA nonbinding mutant (R345A), we identified two residues, V333 and R339, in the VP1 protruding domain as critical mediators of clustering and entry. Mutations of these residues disrupt clustering and endocytosis without affecting HBGA binding, suggesting a role in postattachment processes. While clustering and endocytosis are contingent upon VLP binding to HBGAs, inhibitor studies show they are independent of host protein glycosylation and are driven by lipid raft remodeling regulated by cholesterol and ceramides. Quantitative analyses across multiple GII.4 variants reveal an apparent dichotomy between clustering and nonclustering phenotypes, with clustering variants exhibiting higher entry competence. This distinction offers insight into strain-specific cell entry mechanisms and may aid in identifying the elusive proteinaceous HuNoV cellular receptor(s) supporting targeted therapeutic development.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"9 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasmall inorganic nanoparticles repair damaged meningeal lymphatic vessels to boost Parkinson’s disease therapy","authors":"Mengxiao Han, Yaobao Han, Zhilin Jiang, Yifan Gao, Guozhi Cao, Hao Zhang, Tingting Wang, Zhen Li","doi":"10.1073/pnas.2503434122","DOIUrl":"https://doi.org/10.1073/pnas.2503434122","url":null,"abstract":"Meningeal lymphatic vessels (MLVs) have been identified to associate with various neurological diseases, such as traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and brain tumors. Damage to MLVs can exacerbate the pathological progression of these diseases and significantly impede therapeutic efficacy. Therefore, targeted repair of the damaged MLVs has emerged as an innovative strategy for treating these central nervous system (CNS) diseases. In this study, we find that inorganic Cu <jats:sub>2−</jats:sub> <jats:italic toggle=\"yes\"> <jats:sub>x</jats:sub> </jats:italic> Se nanoparticles, rather than conventional endogenous vascular endothelial growth factor-C (VEGF-C), can repair the damaged MLVs to restore their structure and functions. These nanoparticles not only promote the growth and development of lymphatic vessels but also enhance the drainage capacity of impaired MLVs, thereby facilitating the transport of immune cells and macromolecules through these vessels. Unlike the conventional repair of damaged MLVs, this is an instance where inorganic nanoparticles have been explored to stimulate the expression of VEGF-C and its receptor VEGFR3, thereby promoting the structural and functional recovery of these vessels. The enhanced drainage function of MLVs mediated by Cu <jats:sub>2−</jats:sub> <jats:italic toggle=\"yes\"> <jats:sub>x</jats:sub> </jats:italic> Se nanoparticles significantly alleviates the symptoms of pre-formed fibrils (PFFs)-induced Parkinson’s disease in mice. Collectively, our findings demonstrate that inorganic nanoparticles can promote the growth and development of meningeal lymphatics like VEGF-C, providing a cost-effective and innovative strategy for repairing damaged MLVs to boost the therapeutic efficacy of CNS diseases.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"114 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for Li et al., Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring.","authors":"","doi":"10.1073/pnas.2525325122","DOIUrl":"https://doi.org/10.1073/pnas.2525325122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"42 1","pages":"e2525325122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How to upgrade stolen organelles into permanent plastids: A comparative transcriptomic perspective.","authors":"Norico Yamada,Richard G Dorrell,Ugo Cenci,Peter G Kroth,Vincent Lombard,Brittany N Sprecher","doi":"10.1073/pnas.2514821122","DOIUrl":"https://doi.org/10.1073/pnas.2514821122","url":null,"abstract":"Tertiary plastids derived from diatoms in \"dinotom\" dinoflagellates offer a rare view of organellogenesis in action, while the genomic and metabolic processes underlying their conversion remain poorly understood. Here, we present a comparative transcriptomic analysis of two dinotoms at different plastidial levels: Durinskia capensis at the kleptoplastidy state, alongside its kleptoplastid-source diatom Nitzschia captiva, and its close relative Durinskia kwazulunatalensis at an early permanent state. We show that in both dinotoms, the diatom nucleus retains high transcriptional autonomy, but its expression profile is plastid biased, signaling early host influence. In contrast, only D. kwazulunatalensis exhibits striking signs of genomic reconfiguration in the diatom nucleus: intron insertions, increased guanine (G) and cytosine (C) content, and growing nucleotide similarity to host transcripts. These shifts suggest an incipient nucleomorph-like transformation. Metabolically, only D. kwazulunatalensis expresses a complete hexose phosphate export pathway, suggesting deeper metabolic integration, while both species retain simpler carbohydrate transport routes. Additionally, we propose that diatom karyokinesis might be controlled by a dual mechanism via suppression of key transcription factors at the G1-S checkpoint and nitrate availability. Together, our findings reveal a continuum of plastid integration degrees, from temporary organelle theft to genomic accommodation and metabolic codependence. Dinotoms thus serve not only as evolutionary artifacts but as living laboratories, illuminating how kleptoplastids inch toward permanence.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"674 1","pages":"e2514821122"},"PeriodicalIF":11.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}