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

{"title":"Trigger factor accelerates nascent chain compaction and folding.","authors":"Katharina Till, Anne-Bart Seinen, Florian Wruck, Vanda Sunderlikova, Carla V Galmozzi, Alexandros Katranidis, Bernd Bukau, Günter Kramer, Sander J Tans","doi":"10.1073/pnas.2422678122","DOIUrl":"https://doi.org/10.1073/pnas.2422678122","url":null,"abstract":"<p><p>Conformational control of nascent chains is poorly understood. Chaperones are known to stabilize, unfold, and disaggregate polypeptides away from the ribosome. In comparison, much less is known about the elementary conformational control mechanisms at the ribosome. Yet, proteins encounter major folding and aggregation challenges during translation. Here, using selective ribosome profiling and optical tweezers with correlated single-molecule fluorescence, with dihydrofolate reductase (DHFR) as a model system, we show that the <i>Escherichia coli</i> chaperone trigger factor (TF) accelerates nascent chain folding. TF scans nascent chains by transient binding events, and then locks into a stable binding mode as the chain collapses and folds. This interplay is reciprocal: TF binding collapses nascent chains and stabilizes partial folds, while nascent chain compaction prolongs TF binding. Ongoing translation controls these cooperative effects, with TF-accelerated folding depending on the emergence of a peptide segment that is central to the core DHFR beta-sheet. The folding acceleration we report here impacts processes that depend on folding occurring cotranslationally, including cotranslational protein assembly, protein aggregation, and translational pausing, and may be relevant to other domains of life.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2422678122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715180","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":"Leveraging chromatin packing domains to target chemoevasion in vivo.","authors":"Jane Frederick, Ranya K A Virk, I Chae Ye, Luay M Almassalha, Greta M Wodarcyk, David VanDerway, Ruyi Gong, Cody L Dunton, Tiffany Kuo, Karla I Medina, Margarita Loxas, Jared T Ahrendsen, Demirkan B Gursel, Paola Carrillo Gonzalez, Rikkert J Nap, Saira John, Vasundhara Agrawal, Nicholas M Anthony, John Carinato, Wing Shun Li, Rivaan Kakkaramadam, Surbhi Jain, Shohreh Shahabi, Guillermo A Ameer, Igal G Szleifer, Vadim Backman","doi":"10.1073/pnas.2425319122","DOIUrl":"https://doi.org/10.1073/pnas.2425319122","url":null,"abstract":"<p><p>Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains. However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based model that connects chromatin organization to cell fate decisions, such as survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional activity through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. We conducted a proof-of-concept compound screen using live-cell chromatin imaging to identify several TPRs that synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a framework for enhancing cancer therapies, with broad potential across multiple cancer types.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2425319122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691338","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":"<i>Cdc42</i> defect reveals insights into microvilli organization and function in T cell immunity.","authors":"Won-Chang Soh, Sang-Moo Park, Jeong-Su Park, Hatice Karabulut, Hee-Tae Kang, Sun-Kyoung Kang, Min-Sang Kim, Jihwan Park, Sunjae Lee, Hye-Ran Kim, Chang-Duk Jun","doi":"10.1073/pnas.2505291122","DOIUrl":"https://doi.org/10.1073/pnas.2505291122","url":null,"abstract":"<p><p>Microvilli on T cells differ from those on epithelial cells, exhibiting filopodia-like characteristics that facilitate the clustering of molecules essential for sensing and cell migration. Recently, they have also been recognized as the structures from which T cell immunological synaptosomes (TIS) are released. In this study, we examined a key determinant of microvilli organization during T cell development and explored the functional roles of these structures, particularly in relation to T cell behaviors. During thymocyte maturation, single-positive thymocytes were found to develop more and longer microvilli than double-positive thymocytes. However, the deletion or inhibition of Cdc42, a small Rho family protein, significantly reduced both the number and length of microvilli in single-positive thymocytes, leading to decreased cell mass. This reduction in microvilli correlates with a decrease in antigen recognition, leading to diminished T cell activation and adhesion, as well as reduced TIS production, while intrinsic migratory properties remain unaffected. These findings highlight the filopodia-like characteristics of T cell microvilli. In this context, Cdc42 contributes significantly to microvilli formation, thereby shaping T cell function.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2505291122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715174","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":"Differential representations of spatial location by aperiodic and alpha oscillatory activity in working memory.","authors":"Andrew Bender, Chong Zhao, Edward Vogel, Edward Awh, Bradley Voytek","doi":"10.1073/pnas.2506418122","DOIUrl":"10.1073/pnas.2506418122","url":null,"abstract":"<p><p>Decades of research have shown working memory (WM) relies on sustained prefrontal cortical activity and visual extrastriate activity, particularly in the alpha (8 to 12 Hz) frequency range. This alpha activity tracks the spatial location of WM items, even when spatial position is task-irrelevant and no stimulus is currently being presented. Traditional analyses of putative oscillations using bandpass filters, however, conflate oscillations with nonoscillatory aperiodic activity. Here, we reanalyzed seven human electroencephalography visual WM datasets to test the hypothesis that aperiodic activity, which is thought to reflect the relative contributions of excitatory and inhibitory drive-plays a distinct role in visual WM from true alpha oscillations. To do this, we developed a time-resolved spectral parameterization approach to disentangle oscillations from aperiodic activity during WM encoding and maintenance. Across all seven tasks, totaling 112 participants, we captured the representation of spatial location from total alpha power using inverted encoding models (IEMs), replicating traditional analyses. We then trained separate IEMs to estimate the strength of spatial location representation from aperiodic-adjusted alpha (reflecting just the oscillatory component) and aperiodic activity and find that IEM performance improves for aperiodic-adjusted alpha compared to total alpha power that blends the two signals. We also identify a distinct role for aperiodic activity, where IEM performance trained on aperiodic activity is highest during stimulus presentation, but not during the WM maintenance period. Our results emphasize the importance of controlling for aperiodic activity when studying neural oscillations while uncovering a functional role for aperiodic activity in encoding visual WM information.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2506418122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699265","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":"Effects of the gut microbiota on placental angiogenesis and intrauterine growth in gnotobiotic mice.","authors":"Reyan Coskun, ZeNan L Chang, Athziri Marcial Rodríguez, Haoxin Liu, Jiye Cheng, Yael Alippe, Michael S Diamond, Jeffrey I Gordon","doi":"10.1073/pnas.2426341122","DOIUrl":"https://doi.org/10.1073/pnas.2426341122","url":null,"abstract":"<p><p>Environmental causes of intrauterine growth restriction (IUGR) remain poorly characterized. Here, we compare germ-free (GF) and conventionally raised (CONV-R) mice to assess the effects of the gut microbiota on placental/fetal development at embryonic day (E)11.5 (end of placentation) and E17.5 (near term). Pregnancy- and microbiota-associated changes in gene expression occur along the gut, including those related to angiogenesis, while bacterial composition and fermentation activity remain stable. Placental weights at E11.5 and fetal weights at E17.5 are significantly reduced in GF animals. Compared to CONV-R dams, the GF maternal decidua exhibits similar vascular histomorphometric features at E11.5 and E17.5, and numbers of uterine NK-cells (effectors of vascular remodeling) at E11.5. In contrast, angiogenesis is disturbed in the GF fetal-derived placental compartment (junctional and/or labyrinth zones) at E11.5, as judged by i) increased levels of proangiogenic proteins (angiopoietin-2, FGF-2, follistatin, SDF-1, VEGF-A, VEGF-C); ii) increased levels of phos-VEGFR2 and phos-p38-MAPK yet reduction in phos-ERK1/2; and iii) reduced expression of junctional zone glycoprotein genes associated with angiogenesis and fetal growth, resulting in reduced endothelial cell density at the labyrinth zone at E17.5. Colonization of GF mice before pregnancy with cecal microbiota from CONV-R animals rescues fetal growth and altered transcriptomic, proteomic, and immunohistochemical features in the fetal GF placental compartment. Single-nucleus RNA-sequencing demonstrated increased expression of mitochondrial and ribosomal-associated oxidative stress genes in endothelial cell clusters in the GF fetal placental compartment (E11.5, E17.5), mimicking oxidative stress signatures in human IUGR. These results provide a rationale for seeking microbial targets for treating/preventing IUGR.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2426341122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715176","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":"Retraction for Goswami et al., A bifunctional tRNA import receptor from <i>Leishmania</i> mitochondria.","authors":"","doi":"10.1073/pnas.2517057122","DOIUrl":"https://doi.org/10.1073/pnas.2517057122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2517057122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715179","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":"Seed dispersal disruption limits tropical forest regrowth.","authors":"Evan C Fricke, Susan C Cook-Patton, Charles F Harvey, César Terrer","doi":"10.1073/pnas.2500951122","DOIUrl":"10.1073/pnas.2500951122","url":null,"abstract":"<p><p>Identifying linkages between biodiversity loss and climate change is required for understanding the scope of these interconnected challenges and developing approaches to address them. One crucial yet underexplored aspect is the influence of seed-dispersing animals on forest carbon storage. Here, we show that 81% of tropical trees rely on animals for seed dispersal and that disruption of this process, due to declines in animal diversity and movement, significantly hampers the carbon accumulation potential of regrowing tropical forests. Using a synthesis of animal biodiversity, movement, and seed dispersal data covering thousands of animal species, we developed an index of seed dispersal disruption and modeled its relationship to carbon accumulation observed across 3,026 tropical regrowth plots. Naturally regrowing areas with lowest seed dispersal disruption had aboveground carbon accumulation rates four times higher than those with most severe disruption. Across areas identified as locations suitable for reforestation, current levels of seed dispersal disruption yield a 57% average reduction in local carbon accumulation potential. Tropical regrowth forests currently represent the largest land-based carbon sink; ongoing animal biodiversity losses diminish their ability to recover naturally from disturbances and therefore threaten their climate mitigation potential. These results advance understanding of animal biodiversity's impact on carbon dynamics and emphasize the need to address biodiversity loss and climate change together.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2500951122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699276","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 publics in small-island states view climate change and international responses to it.","authors":"Matto Mildenberger, Sara M Constantino, Paasha Mahdavi, Parrish Bergquist, Gabriel De Roche, Emma Franzblau, Cesar Martinez-Alvarez, Ingmar Sturm","doi":"10.1073/pnas.2415324122","DOIUrl":"https://doi.org/10.1073/pnas.2415324122","url":null,"abstract":"<p><p>Climate change caused by carbon pollution from the world's largest economies poses an existential threat to small-island states and territories this century. These places bear virtually no responsibility for climate change but will face sea-level rise, fresh water resource degradation, and intensified storms that will kill or dislocate exposed publics, and damage local economies. To alleviate this crisis, the global community has begun discussing who is responsible for climate mitigation and adaptation costs for those affected by climate change, in addition to continued debates around the distribution of responsibility for climate change. Missing from this analysis, however, are systematic efforts to elicit the preferences and perceptions of publics in these threatened small-island states and territories. Here, we report results from a large-sample (n [Formula: see text] 14,710) cross-national survey of publics living in climate-vulnerable states and territories, conducted in June-July 2022. By quota sampling through Facebook's ad platform, we generate survey samples at the national or territorial level for publics in 55 small-island states, territories, and subnational regions in the South Pacific, Indian Ocean, and Caribbean. We find widespread awareness and concern about the threat posed by climate change and sea-level rise, in contrast to what existing research finds in the Global North. We also find that climate-vulnerable publics believe their home governments, large polluters, and former colonial powers are all responsible for helping to manage the climate crisis, irrespective of these actors' relative carbon emissions. These findings fill an important gap by depicting climate beliefs among the communities at the frontlines of climate change.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 30","pages":"e2415324122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715177","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":"Mechanistic insights into the iron-sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the E3 ligase HERC2.","authors":"Haobo Liu,Liqiang Shen,Xinyu Gong,Xindi Zhou,Yichao Huang,Yuqian Zhou,Zhenpeng Guo,Hanbo Guo,Shichao Wang,Lifeng Pan","doi":"10.1073/pnas.2510269122","DOIUrl":"https://doi.org/10.1073/pnas.2510269122","url":null,"abstract":"NCOA4, a dedicated autophagy receptor for mediating selective autophagy of ferritin (ferritinophagy), plays a vital role in maintaining cellular iron homeostasis. The cellular abundance of NCOA4 is regulated by the E3 ligase HERC2 that can specifically target NCOA4 for proteasomal degradation under iron-replete conditions. However, the detailed molecular mechanism governing the iron-dependent recognition of NCOA4 by HERC2 remains elusive. Here, using multidisciplinary approaches, we systematically characterize the HERC2-binding domain (HBD) of NCOA4 and its interaction with HERC2. We uncover that NCOA4 HBD harbors a [2Fe-2S] cluster and can exist in two different states, the apo-form state and the [2Fe-2S] cluster-bound state. Moreover, we unravel that HERC2 can effectively recognize the [2Fe-2S] cluster-bound NCOA4 HBD through its Cullin-7-PARC-HERC2 (CPH) domain and iron-sulfur cluster-dependent NCOA4-binding domain (INBD) with a synergistic binding mode. The determined crystal structures of HERC2(2540-2700) and its complex with the [2Fe-2S] cluster-bound NCOA4 HBD together with relevant biochemical and cellular results not only elucidate how NCOA4 HBD specifically senses cellular iron level by binding a [2Fe-2S] cluster but also reveal the molecular basis underlying the specific interaction of HERC2 with the [2Fe-2S] cluster-bound NCOA4 HBD. In summary, our findings provide mechanistic insights into the iron-dependent turnover of NCOA4 by HERC2 and expand our understanding of the regulatory mechanism of NCOA4-mediated ferritinophagy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"18 1","pages":"e2510269122"},"PeriodicalIF":11.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693173","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":"ATP synthesis driven by atmospheric hydrogen concentrations.","authors":"Sarah Soom,Stefan Urs Moning,Gregory M Cook,James P Lingford,Ashleigh Kropp,Sieu Tran,Rhys Grinter,Chris Greening,Christoph von Ballmoos","doi":"10.1073/pnas.2506353122","DOIUrl":"https://doi.org/10.1073/pnas.2506353122","url":null,"abstract":"All cells require a continuous supply of the universal energy currency, adenosine triphosphate (ATP), to drive countless cellular reactions. The universally conserved F1Fo-ATP synthase regenerates ATP from ADP and Pi by harnessing a transmembrane electrochemical proton gradient (pmf). Bacteria have evolved diverse pmf-forming strategies using light, organic, and inorganic energy sources. Recently, we proposed that many bacteria survive using atmospheric trace gases to produce ATP when limited for other energy sources. However, direct evidence that atmospheric energy sources are sufficient to generate pmf or drive ATP synthesis is still lacking. Here, we show that the membrane-associated hydrogen:quinone oxidoreductase Huc from Mycobacterium smegmatis can enable ATP synthesis from air. Purified Huc couples H2 oxidation to the reduction of various ubiquinone and menaquinone analogues. We designed a minimal respiratory chain in which Huc interacts with liposomes containing the nonpumping, but pmf-generating, bd-I oxidase and F1Fo-ATP synthase from Escherichia coli. Our experiments show that passive hydrogen exchange from air to solution is sufficient for the electron transfer and pmf generation required to accumulate ATP. By combining continuous culture bioenergetics measurements with theoretical calculations, we show this process is sufficient for mycobacteria to sustain pmf and ATP synthesis (two ATP molecules per H2 oxidized) for maintenance energy requirements during nutrient starvation. These findings confirm that atmospheric energy sources can be dependable 'lifeline' substrates that enable continuous energy conservation during nutrient starvation. In addition, this work provides a unique tool for ATP production in synthetic applications, which unlike other approaches is traceless without by-product accumulation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"75 1","pages":"e2506353122"},"PeriodicalIF":11.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693390","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}