Proceedings of the National Academy of Sciences of the United States of America最新文献_第4页

Correction for Luo et al., An acetyltransferase moonlights as a regulator of the RNA binding repertoire of the RNA chaperone Hfq in Escherichia coli.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-07 DOI: 10.1073/pnas.2501041122

引用次数: 0

Correction for Rachuri et al., Mutational analysis of an antimalarial drug target, PfATP4.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-07 DOI: 10.1073/pnas.2501024122

引用次数: 0

ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2416578122

Nicholas J Constantino, Caitlin M Carroll, Holden C Williams, Hemendra J Vekaria, Carla M Yuede, Kai Saito, Patrick W Sheehan, J Andy Snipes, Marcus E Raichle, Erik S Musiek, Patrick G Sullivan, Josh M Morganti, Lance A Johnson, Shannon L Macauley

{"title":"ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep.","authors":"Nicholas J Constantino, Caitlin M Carroll, Holden C Williams, Hemendra J Vekaria, Carla M Yuede, Kai Saito, Patrick W Sheehan, J Andy Snipes, Marcus E Raichle, Erik S Musiek, Patrick G Sullivan, Josh M Morganti, Lance A Johnson, Shannon L Macauley","doi":"10.1073/pnas.2416578122","DOIUrl":"10.1073/pnas.2416578122","url":null,"abstract":"Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking KATP channel activity (e.g., Kir6.2-/- mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2-/- mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of sleep/wake states and providing the metabolic flexibility to transition between states.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2416578122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441697","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}

引用次数: 0

Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2414738122

Matthew J Klauer, Katherine L Hall, Caitlin A D Jagla, Nikoleta G Tsvetanova

{"title":"Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR.","authors":"Matthew J Klauer, Katherine L Hall, Caitlin A D Jagla, Nikoleta G Tsvetanova","doi":"10.1073/pnas.2414738122","DOIUrl":"10.1073/pnas.2414738122","url":null,"abstract":"G protein-coupled receptors (GPCRs) modulate various physiological functions by rewiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific posttranscriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 gene targets of adrenergic receptor activity for which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs and report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets, we find significant enrichment of genes with 5' terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. This site-selective crosstalk between the pathways is observed in multiple cell models with native β2-ARs, across a range of endogenous and synthetic adrenergic agonists, and for other GPCRs with intracellular activity. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2414738122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441665","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}

引用次数: 0

PSKH1 kinase activity is differentially modulated via allosteric binding of Ca²⁺ sensor proteins.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2420961122

Christopher R Horne, Toby A Dite, Samuel N Young, Lucy J Mather, Laura F Dagley, Jared L Johnson, Tomer M Yaron-Barir, Emily M Huntsman, Leonard A Daly, Dominic P Byrne, Antonia L Cadell, Boaz H Ng, Jumana Yousef, Dylan H Multari, Lianju Shen, Luke M McAloon, Gerard Manning, Mark A Febbraio, Anthony R Means, Lewis C Cantley, Maria C Tanzer, David R Croucher, Claire E Eyers, Patrick A Eyers, John W Scott, James M Murphy

{"title":"PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins.","authors":"Christopher R Horne, Toby A Dite, Samuel N Young, Lucy J Mather, Laura F Dagley, Jared L Johnson, Tomer M Yaron-Barir, Emily M Huntsman, Leonard A Daly, Dominic P Byrne, Antonia L Cadell, Boaz H Ng, Jumana Yousef, Dylan H Multari, Lianju Shen, Luke M McAloon, Gerard Manning, Mark A Febbraio, Anthony R Means, Lewis C Cantley, Maria C Tanzer, David R Croucher, Claire E Eyers, Patrick A Eyers, John W Scott, James M Murphy","doi":"10.1073/pnas.2420961122","DOIUrl":"10.1073/pnas.2420961122","url":null,"abstract":"Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed in prostate, lung, and kidney cancers. However, little is known about PSKH1 regulatory mechanisms, leading to its classification as a \"dark\" kinase. Here, we used biochemistry and mass spectrometry to define PSKH1's consensus substrate motif, protein interactors, and how interactors, including Ca2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca2+-Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca2+ sensor of the Cab45, Reticulocalbin, Erc55, Calumenin (CREC) family, Reticulocalbin-3, suppressed PSKH1 catalytic activity. In addition to antagonistic regulation of the PSKH1 kinase domain by Ca2+ sensing proteins, we identified UNC119B as a protein interactor that activates PSKH1 via direct engagement of the kinase domain. Our findings identify complementary allosteric mechanisms by which regulatory proteins tune PSKH1's catalytic activity and raise the possibility that different Ca2+ sensors may act more broadly to tune kinase activities by detecting and decoding extremes of intracellular Ca2+ concentrations.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2420961122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441735","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}

引用次数: 0

OsNLP3 and OsPHR2 orchestrate direct and mycorrhizal pathways for nitrate uptake by regulating NAR2.1-NRT2s complexes in rice.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2416345122

Shuangshuang Wang, Hanghang Ye, Congfan Yang, Yan Zhang, Jiawen Pu, Yuhan Ren, Kun Xie, Lingxiao Wang, Dechao Zeng, Haoqiang He, Haoyan Ji, Luis Rafael Herrera-Estrella, Guohua Xu, Aiqun Chen

{"title":"OsNLP3 and OsPHR2 orchestrate direct and mycorrhizal pathways for nitrate uptake by regulating NAR2.1-NRT2s complexes in rice.","authors":"Shuangshuang Wang, Hanghang Ye, Congfan Yang, Yan Zhang, Jiawen Pu, Yuhan Ren, Kun Xie, Lingxiao Wang, Dechao Zeng, Haoqiang He, Haoyan Ji, Luis Rafael Herrera-Estrella, Guohua Xu, Aiqun Chen","doi":"10.1073/pnas.2416345122","DOIUrl":"10.1073/pnas.2416345122","url":null,"abstract":"Nitrogen (N) is the most important essential nutrient required by plants. Most land plants have evolved two N uptake pathways, a direct root pathway and a symbiotic pathway, via association with arbuscular mycorrhizal (AM) fungi. However, the interaction between the two pathways is ambiguous. Here, we report that OsNAR2.1-OsNRT2s, the nitrate (NO3-) transporter complexes with crucial roles in direct NO3- uptake, are also recruited for symbiotic NO3- uptake. OsNAR2.1 and OsNRT2.1/2.2 are coregulated by NIN-like protein 3 (OsNLP3), a key regulator in NO3- signaling, and OsPHR2, a major regulator of phosphate starvation responses. More importantly, AM symbiosis induces expression of OsNAR2.1-OsNRT2s, OsNLP3, and OsSPX4, encoding an intracellular Pi sensor, in arbuscular-containing cells, but weakens their expression in the epidermis. OsNAR2.1 and OsNLP3 can activate both mycorrhizal NO3- uptake and mycorrhization efficiency. Overall, we demonstrate that OsNLP3 and OsPHR2 orchestrate the direct and mycorrhizal NO3- uptake pathways by regulating the NAR2.1-NRT2s complexes in rice.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2416345122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441746","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}

引用次数: 0

Identification of AK4 and RHOC as potential oncogenes addicted by adult T cell leukemia.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-21 DOI: 10.1073/pnas.2416412122

Benquan Liu, Jun-Ichirou Yasunaga, Yi Liang, Ruoning Zhou, Sikai Yang, Xiaoyi Yuan, Jie Liu, Xiaorui Zuo, Michi Miura, Yusuke Higuchi, Takashi Matsumoto, Kosuke Toyoda, Masao Matsuoka, Guangyong Ma

{"title":"Identification of AK4 and RHOC as potential oncogenes addicted by adult T cell leukemia.","authors":"Benquan Liu, Jun-Ichirou Yasunaga, Yi Liang, Ruoning Zhou, Sikai Yang, Xiaoyi Yuan, Jie Liu, Xiaorui Zuo, Michi Miura, Yusuke Higuchi, Takashi Matsumoto, Kosuke Toyoda, Masao Matsuoka, Guangyong Ma","doi":"10.1073/pnas.2416412122","DOIUrl":"https://doi.org/10.1073/pnas.2416412122","url":null,"abstract":"Adult T cell leukemia (ATL) is a highly aggressive T cell malignancy characterized by human T cell leukemia virus type 1 (HTLV-1) infection. ATL has a very poor prognosis and lacks satisfactory treatments; therefore, it is critical to identify potential targets in ATL cells in order to develop effective targeted therapeutics. Here, we report the identification of two oncogenes, AK4 and RHOC, as target genes of miR-455-3p, a tumor-suppressive microRNA in ATL patients. Importantly, AK4 and RHOC are highly expressed in ATL and exhibit oncogenic potentials in vitro and in vivo. Interestingly, transcriptome and metabolome analyses reveal a functional overlap of AK4 and RHOC, including activating oncogenic pathways such as Myc targets and deregulating lipid metabolism such as enhancing the production of sphingomyelin, a tumor-promoting lipid. In particular, compared to other types of T cell malignancy such as T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma (CTCL), ATL is sensitive to sphingomyelin inhibition and AK4 or RHOC depletion. Altogether, we report a distinct dependency of ATL on AK4 and RHOC oncogenes and an oncometabolite sphingomyelin, which together represent targetable vulnerabilities of ATL that could be exploited for developing effective therapeutics.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2416412122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468534","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}

引用次数: 0

Correction for Talukder et al., Olfaction with legs-Spiders use wall-pore sensilla for pheromone detection.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-06 DOI: 10.1073/pnas.2501234122

引用次数: 0

Tracking proteasome degradation: A cross-organ analysis via intact degradomics mass spectrometry.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2419607122

Katharina I Zittlau, Daniel Zachor-Movshovitz, Yegor Leushkin, Roy Schimmel Brener, David Morgenstern, Gili Ben-Nissan, Michal Sharon

{"title":"Tracking proteasome degradation: A cross-organ analysis via intact degradomics mass spectrometry.","authors":"Katharina I Zittlau, Daniel Zachor-Movshovitz, Yegor Leushkin, Roy Schimmel Brener, David Morgenstern, Gili Ben-Nissan, Michal Sharon","doi":"10.1073/pnas.2419607122","DOIUrl":"10.1073/pnas.2419607122","url":null,"abstract":"The proteasome is a multisubunit degradation machinery that is essential for maintaining protein homeostasis by breaking down unnecessary or damaged proteins into peptides. While most of these peptides are further processed into amino acids, a subset evades complete degradation and plays key roles in biological processes such as antigen presentation, signaling, and apoptosis. However, the variability in peptide lengths and the diverse composition of proteasomes make their comprehensive identification and characterization particularly challenging. Here, we present a method that enables real-time identification of generated peptides, as well as uncleaved and partially cleaved protein substrates, revealing the processive nature of protein proteasomal degradation. Our intact degradomics workflow is based on intact mass spectrometry measurements and treats the enzymatically produced peptides as if they were generated within the mass spectrometer, akin to top-down products. We applied this approach to determine the kinetic profile of proteasome degradation and compare the real-time activity of proteasomes isolated from different mouse organs, uncovering distinct functionalities of the complex. Overall, this method offers a valuable tool for studying peptide degradation products across various proteasome configurations, while also enabling the investigation of how interacting proteins, inhibitors, and activators influence proteasome activity. Furthermore, its adaptability makes it applicable to a wide range of other proteolytic complexes, broadening its potential impact in the field.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2419607122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441778","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}

引用次数: 0

Volumetric imaging of the 3D orientation of cellular structures with a polarized fluorescence light-sheet microscope.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-25 Epub Date: 2025-02-21 DOI: 10.1073/pnas.2406679122

Talon Chandler, Min Guo, Yijun Su, Jiji Chen, Yicong Wu, Junyu Liu, Atharva Agashe, Robert S Fischer, Shalin B Mehta, Abhishek Kumar, Tobias I Baskin, Valentin Jaumouillé, Huafeng Liu, Vinay Swaminathan, Amrinder S Nain, Rudolf Oldenbourg, Patrick J La Riviere, Hari Shroff

{"title":"Volumetric imaging of the 3D orientation of cellular structures with a polarized fluorescence light-sheet microscope.","authors":"Talon Chandler, Min Guo, Yijun Su, Jiji Chen, Yicong Wu, Junyu Liu, Atharva Agashe, Robert S Fischer, Shalin B Mehta, Abhishek Kumar, Tobias I Baskin, Valentin Jaumouillé, Huafeng Liu, Vinay Swaminathan, Amrinder S Nain, Rudolf Oldenbourg, Patrick J La Riviere, Hari Shroff","doi":"10.1073/pnas.2406679122","DOIUrl":"https://doi.org/10.1073/pnas.2406679122","url":null,"abstract":"Polarized fluorescence microscopy is a valuable tool for measuring molecular orientations in biological samples, but techniques for recovering three-dimensional orientations and positions of fluorescent ensembles are limited. We report a polarized dual-view light-sheet system for determining the diffraction-limited three-dimensional distribution of the orientations and positions of ensembles of fluorescent dipoles that label biological structures. We share a set of visualization, histogram, and profiling tools for interpreting these positions and orientations. We model the distributions based on the polarization-dependent efficiency of excitation and detection of emitted fluorescence, using coarse-grained representations we call orientation distribution functions (ODFs). We apply ODFs to create physics-informed models of image formation with spatio-angular point-spread and transfer functions. We use theory and experiment to conclude that light-sheet tilting is a necessary part of our design for recovering all three-dimensional orientations. We use our system to extend known two-dimensional results to three dimensions in FM1-43-labeled giant unilamellar vesicles, fast-scarlet-labeled cellulose in xylem cells, and phalloidin-labeled actin in U2OS cells. Additionally, we observe phalloidin-labeled actin in mouse fibroblasts grown on grids of labeled nanowires and identify correlations between local actin alignment and global cell-scale orientation, indicating cellular coordination across length scales.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2406679122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468542","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}

引用次数: 0