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

筛选
英文 中文
Rewarding touch limits lifespan through neural to intestinal signaling. 奖励触摸通过神经到肠道的信号限制了寿命。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2423780122
Elizabeth S Kitto,Safa Beydoun,Scott F Leiser
{"title":"Rewarding touch limits lifespan through neural to intestinal signaling.","authors":"Elizabeth S Kitto,Safa Beydoun,Scott F Leiser","doi":"10.1073/pnas.2423780122","DOIUrl":"https://doi.org/10.1073/pnas.2423780122","url":null,"abstract":"In multicellular organisms, sensory perception affects many aspects of behavior and physiology. Perception of environmental stressors like food scarcity often leads to physiological changes that promote survival and slow aging. However, recent work shows that perception of attractive food smells can block the health benefits of dietary restriction in multiple model organisms. While it is known that sensory perception and cell nonautonomous signaling can modulate health and longevity, our knowledge of the specific sensory cues and mechanistic pathways that define this signaling is still limited. Here we find that the sense of touch interacts with nutritional state to modulate lifespan in Caenorhabditis elegans. Worms subjected to dietary restriction are shorter-lived when they perceive tactile stimuli that mimic bacterial food and/or protective soil. Touch modulation of dietary restriction requires putative mechanoreceptor proteins, the neurotransmitters dopamine and tyramine/adrenaline, and the neuropeptides INS-11 and GnRH. Ultimately, the touch circuit regulates the longevity effectors DAF-2/IGF1R and FMO-2/FMO5. These results establish a physiological touch circuit and connect neural reward pathways to the growth and reproductive axes. Finding that texture mechanosensation can modulate longevity suggests a role for touch in lifespan.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"42 1","pages":"e2423780122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351463","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
Squamous cell carcinoma antigen-1/SerpinB3 is an endogenous skin injury response element. 鳞状细胞癌抗原-1/SerpinB3是一种内源性皮肤损伤反应因子。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2415164122
Jordan R Yaron,Shubham Pallod,Sepideh Nezhadi,Holly M Gildar,Jayda Hylton-Pelaia,Jordan Roberts,Jacquelyn Kilbourne,Kaushal Rege
{"title":"Squamous cell carcinoma antigen-1/SerpinB3 is an endogenous skin injury response element.","authors":"Jordan R Yaron,Shubham Pallod,Sepideh Nezhadi,Holly M Gildar,Jayda Hylton-Pelaia,Jordan Roberts,Jacquelyn Kilbourne,Kaushal Rege","doi":"10.1073/pnas.2415164122","DOIUrl":"https://doi.org/10.1073/pnas.2415164122","url":null,"abstract":"The squamous cell carcinoma antigen SerpinB3 is a serum-circulating biomarker of epithelial cancers associated with high metastasis, treatment resistance, and poor prognosis. Despite its clinical significance, the endogenous role of SerpinB3 has remained undefined. Here, we identify SerpinB3 as a mediator of epithelial wound healing. Injury induces SerpinB3 expression in vitro and in vivo in the migrating epidermal tongue; overexpression of the protein promotes epithelial-to-mesenchymal transition-like changes. Recombinant Serpinb3a, the mouse ortholog, enhances re-epithelialization in vitro and accelerates wound closure and collagen remodeling in vivo. These findings reveal a physiological function for SerpinB3 in epithelial repair and suggest that its expression in cancer, chronic wounds, and inflammatory diseases may reflect reactivation of a conserved wound response program-positioning SerpinB3 as a compelling therapeutic target.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"50 1","pages":"e2415164122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351526","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
Differential O-glucose elongation on a specific EGF repeat within the canonical ligand-binding domain regulates DLL1/4-NOTCH1 signaling. 典型配体结合域内特定EGF重复序列上的差异o -葡萄糖延伸调节DLL1/4-NOTCH1信号传导。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2504827122
Yohei Tsukamoto,Kazuhiro Aoki,Yuichi Kama,Hiroyuki Hosokawa,Wataru Saiki,Natsumi Tsukamoto,Koki Kato,Yohei Hosokawa,Rie Sato,Naoki Uesugi,Yuki Fujita,Kana Fukazawa,Daichi Funada,Fuga Suzuki,Yuuki Kurebayashi,Yusuke Urata,Sae Uchiyama,Weiwei Wang,Akira Minami,Tadanobu Takahashi,Michael Tiemeyer,Yoshiki Narimatsu,Tetsuya Okajima,Hideyuki Takeuchi
{"title":"Differential O-glucose elongation on a specific EGF repeat within the canonical ligand-binding domain regulates DLL1/4-NOTCH1 signaling.","authors":"Yohei Tsukamoto,Kazuhiro Aoki,Yuichi Kama,Hiroyuki Hosokawa,Wataru Saiki,Natsumi Tsukamoto,Koki Kato,Yohei Hosokawa,Rie Sato,Naoki Uesugi,Yuki Fujita,Kana Fukazawa,Daichi Funada,Fuga Suzuki,Yuuki Kurebayashi,Yusuke Urata,Sae Uchiyama,Weiwei Wang,Akira Minami,Tadanobu Takahashi,Michael Tiemeyer,Yoshiki Narimatsu,Tetsuya Okajima,Hideyuki Takeuchi","doi":"10.1073/pnas.2504827122","DOIUrl":"https://doi.org/10.1073/pnas.2504827122","url":null,"abstract":"Three types of O-linked glycosylation-O-glucose, O-fucose, and O-N-acetylglucosamine- are crucial for the function of Notch receptors, which regulate critical cell fate determination processes in a wide variety of contexts. O-Glucose glycans are transferred to serine residues located between the first and second conserved cysteines within the epidermal growth factor-like (EGF) repeats in the Notch extracellular domain. Previously, O-glucose glycans were shown to be extended to a trisaccharide structure with two xyloses via α1-3 linkages. Our recent studies, however, indicated that the O-glucose glycan on NOTCH1 EGF10 can be extended by hexose and Neu5Ac. Here, we demonstrated that this hexose- and Neu5Ac-extended glycan has a 3'-sialyllactose-like structure synthesized by specific members of two isoenzyme families, B4GALT1 and ST3GAL4. Using mass spectrometry, we identified this modification exclusively on NOTCH1 EGF10 and the analogous NOTCH3 EGF9 domain, with no detection in any other EGF domains in NOTCH1, NOTCH2, and NOTCH3. Sequence comparison and mutagenesis experiments identified one amino acid at position -2 of the fourth cysteine (C4-2) in the EGF domain as crucial for the galactose elongation of O-glucose glycans. We further demonstrated that this site-specific elongation of O-glucose on NOTCH1 EGF10 significantly impacts ligand binding and signal transduction of NOTCH1. In the context of early T cell development, the C4-2 mutants NOTCH1 A396Y and A396F enhance T cell differentiation through DLL1- and DLL4-dependent NOTCH1 signaling. Our findings contribute to the understanding of the intricate regulatory mechanisms of Notch receptor function mediated by distinct positions and structures of O-glycans.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"52 1","pages":"e2504827122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351824","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
Nir2 crystal structures reveal a phosphatidic acid-sensing mechanism at ER-PM contact sites. Nir2晶体结构揭示了在ER-PM接触位点的磷脂酸敏感机制。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2516849122
Dongyoung Kim,Seowhang Lee,Youngsoo Jun,Changwook Lee
{"title":"Nir2 crystal structures reveal a phosphatidic acid-sensing mechanism at ER-PM contact sites.","authors":"Dongyoung Kim,Seowhang Lee,Youngsoo Jun,Changwook Lee","doi":"10.1073/pnas.2516849122","DOIUrl":"https://doi.org/10.1073/pnas.2516849122","url":null,"abstract":"Agonist-induced activation of phosphoinositide-specific phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to diacylglycerol (DAG) at the inner leaflet of the plasma membrane (PM). DAG can be enzymatically transformed into phosphatidic acid (PA) and accumulated at the PM. PYK2 N-terminal domain-interacting receptor 2 (Nir2) mediates the formation of ER-PM membrane contact sites (MCSs) by specifically recognizing PA at the PM and directly interacting with ER membrane protein vesicle-associated membrane protein-associated proteins (VAPs). The N-terminal phosphatidylinositol transfer protein domain of Nir2 facilitates PI/PA exchange at ER-PM MCSs to maintain PI and PA levels. Here, we reveal the mechanisms by which Nir2 senses phosphatidic acid (PA) and associates with membranes, based on three crystal structures of its C-terminal Lipin/Ned1/Smp2 (LNS2) domain bound to PA, the diphenylalanine [FF]-containing acidic tract (FFAT) motif complexed with vesicle-associated membrane protein-associated protein B/C (VAPB), and the Asp-Asp-His-Asp (DDHD) domain. The C-terminal LNS2 domain of Nir2 directly interacts with the phosphate in the headgroup of PA via hydrogen bonds involving S1025, T1065, K1103, and K1126. Formation of a salt bridge between E355 in Nir2 and R55 in VAPB is essential for Nir2 FFAT-VAPB interaction. The central DDHD domain of Nir2 forms a twofold symmetric dimer, and this self-association contributes to stable and tight membrane association. These findings reveal how Nir2-mediated ER-PM MCS formation maintains continued PI(4,5)P2-dependent PLC signaling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"2 1","pages":"e2516849122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351866","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
Aberrant X chromosome dosage compensation causes hybrid male inviability in Caenorhabditis. 异常X染色体剂量补偿导致隐杆线虫病杂种雄性不育。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2507166122
Yongbin Li,Yimeng Gao,Jiaonv Ma,Yifan Gao,Jiemei Tang,Rui Yang,Jiajia Wang,Wangyan Zhou,Hantang Zhang,Wenhua Shao,Zhijin Liu,Zhongying Zhao,Xiao Liu
{"title":"Aberrant X chromosome dosage compensation causes hybrid male inviability in Caenorhabditis.","authors":"Yongbin Li,Yimeng Gao,Jiaonv Ma,Yifan Gao,Jiemei Tang,Rui Yang,Jiajia Wang,Wangyan Zhou,Hantang Zhang,Wenhua Shao,Zhijin Liu,Zhongying Zhao,Xiao Liu","doi":"10.1073/pnas.2507166122","DOIUrl":"https://doi.org/10.1073/pnas.2507166122","url":null,"abstract":"Zygotic reproductive isolation frequently initiates with hybrid incompatibility in the heterogametic sex, such as males in XX/XY systems. The genetic basis of hybrid male incompatibility has long remained elusive. Here, we show that crosses of Caenorhabditis nigoni males with C. briggsae females result in insufficient expression of Cbr-xol-1, an X-linked master switch responsible for intimately linked sex determination and dosage compensation pathways, consequently triggering aberrant X-chromosome repression in males, and ultimately leading to embryonic inviability. In contrast, male embryos from the reciprocal cross maintain normal expression level of C. nigoni xol-1 genes, consistent with their viability. We further demonstrate that the cis-regulatory regions of Cbr-xol-1 and Cni-xol-1 have functionally diverged. Finally, X transcription is also aberrantly repressed in lethal hybrid male embryos from crosses between gonochoristic species C. latens and C. remanei. Our results suggest an evolutionary scenario in which incompatibility of the dosage compensation system leads to reproductive isolation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"26 1","pages":"e2507166122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351462","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
A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression. PHF19-YTHDC1凝聚物将ezh2介导的基因抑制转换为前列腺癌进展的激活。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2510386122
Shuai Yuan,Dao-Jing Ming,Jiapeng He,Meng-Yang Liu,Shao-Hua He,Hong Weng,Shu Xi,Jin-Hui Zhang,Ming-Hui Shi,Jin-Long Cui,Lu-Yao Li,Haozhe Zhang,Dan-Qi Wang,Fei Li,Meng-Meng Guo,Yi Cai,Shi-Di Tang,Shuang-Ying Wang,Xing-Huan Wang,Xian-Tao Zeng,Hailiang Hu
{"title":"A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression.","authors":"Shuai Yuan,Dao-Jing Ming,Jiapeng He,Meng-Yang Liu,Shao-Hua He,Hong Weng,Shu Xi,Jin-Hui Zhang,Ming-Hui Shi,Jin-Long Cui,Lu-Yao Li,Haozhe Zhang,Dan-Qi Wang,Fei Li,Meng-Meng Guo,Yi Cai,Shi-Di Tang,Shuang-Ying Wang,Xing-Huan Wang,Xian-Tao Zeng,Hailiang Hu","doi":"10.1073/pnas.2510386122","DOIUrl":"https://doi.org/10.1073/pnas.2510386122","url":null,"abstract":"EZH2, a core component of PRC2 complex, silences global gene expression by tri-methylating histone H3K27. It remains an elusive question that EZH2 hyperexpression discords with its H3K27me3 activity of gene suppression in advanced prostate cancer. Here, we report a nascent RNA-dependent PHF19-YTHDC1 condensate capable of switching EZH2-mediated gene suppression to activation during prostate cancer progression. We found that the long isoform of PRC2 accessory subunit PHF19, PHF19L, was highly expressed in advanced prostate cancer that promoted the tumor progression and hormonal therapy resistance. Mechanistically, PHF19L was recruited to the m6A modified nascent RNA through YTHDC1 and formed a liquid-like YTHDC1-PHF19L condensate that pulled the EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and the activated expression of EZH2-repressed genes. Therefore, our study reveals a biomolecular condensate that modulates the switch from EZH2-mediated epigenetic gene silence to activation during the progression of prostate cancer.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"109 1","pages":"e2510386122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351471","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
Exceptional diversity of allorecognition receptors in a nonvertebrate chordate reveals principles of innate allelic discrimination. 非脊椎动物脊索动物异体识别受体的异常多样性揭示了先天等位基因歧视的原理。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2519372122
Henry Rodriguez-Valbuena,Jorge Salcedo,Olivier De Thier,Jean Francois Flot,Stefano Tiozzo,Anthony W De Tomaso
{"title":"Exceptional diversity of allorecognition receptors in a nonvertebrate chordate reveals principles of innate allelic discrimination.","authors":"Henry Rodriguez-Valbuena,Jorge Salcedo,Olivier De Thier,Jean Francois Flot,Stefano Tiozzo,Anthony W De Tomaso","doi":"10.1073/pnas.2519372122","DOIUrl":"https://doi.org/10.1073/pnas.2519372122","url":null,"abstract":"Highly polymorphic allorecognition systems have been characterized in numerous invertebrate species, and exhibit discriminatory capabilities reminiscent of vertebrate adaptive immunity. As these systems utilize germline encoded receptors, the mechanisms underlying allelic discrimination are unknown. The invertebrate chordate, Botryllus schlosseri, undergoes a natural transplantation reaction controlled by a highly polymorphic, polygenic locus (called the fuhc) with over 1,000 allelic haplotypes found worldwide. Two individuals are compatible if they share one or both fuhc alleles, and we had found that polymorphic discrimination is due to the integration of signals from two allorecognition receptors encoded within the fuhc locus, called fester and uncle fester. Here we show that these two receptors are members of an extended family consisting of >35 genes, now called the Fester family (FF), and coexpressed with members of another diverse gene family, the fester coreceptors (FcoR). Both FF and FcoR are Immunoglobulin superfamily members and each FcoR encodes conserved tyrosine signal transduction motifs, including ITIMs or hemITAMs. FF and FcoR are expressed and encoded as cognate pairs in two polymorphic haplotypes: one within the fuhc locus, and another on a separate chromosome, and remarkably, copy number variation between haplotypes is of gene pairs. Furthermore, two FcoR genes can swap ITIMs and hemITAMs by alternative splicing, suggesting that dynamic tuning of activating and inhibitory signaling is required for allelic discrimination. These results indicate that conserved signal processing mechanisms are the foundation of both allelic discrimination in Botryllus, and recurring convergent evolution of allorecognition receptors observed from invertebrates to mammals.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"16 1","pages":"e2519372122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351864","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
Genetic regulation of the estrogen receptor and inherited predisposition to breast cancer. 雌激素受体的基因调控与乳腺癌的遗传易感性。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2517736122
Sarah B Pierce,Hannah Kortbawi,Suleyman Gulsuner,Jessica B Mandell,Ming K Lee,Tom Walsh,Mary-Claire King
{"title":"Genetic regulation of the estrogen receptor and inherited predisposition to breast cancer.","authors":"Sarah B Pierce,Hannah Kortbawi,Suleyman Gulsuner,Jessica B Mandell,Ming K Lee,Tom Walsh,Mary-Claire King","doi":"10.1073/pnas.2517736122","DOIUrl":"https://doi.org/10.1073/pnas.2517736122","url":null,"abstract":"For many families severely affected with breast cancer, no inherited causal allele has been detected in any tumor suppressor gene. In an effort to understand the genetics underlying breast cancer in these families, we evaluated 136 such families for coinheritance of breast cancer with each of 79 common variants reported as high-confidence \"risk alleles\" for breast cancer by meta-analyses of genome-wide association studies. Simulations based on allele frequencies and family structures revealed one (and only one) of these 79 variants to cosegregate with breast cancer in the families significantly more frequently than expected by chance. This variant (rs2046210) is located 180 kb proximal to ESR1, encoding the estrogen receptor alpha. Reporter assays in MCF7 cells revealed enhancement by the genomic segment at this site of activity of ESR1 promoters, but no difference in effect among alternative haplotypes. In contrast, the 600 kb genomic region including ESR1 and rs2046210 harbored 11 rare variants, each of which cosegregated with breast cancer in one or a few families. For 9 of these 11 variants, reporter assays indicated significant allele-specific effects on ESR1 promoters, with the breast-cancer-linked allele of each variant yielding higher promoter activity. At the site with the most striking effect, the breast-cancer-linked allele was associated with increased binding by transcription factor AP2-gamma TFAP2C in both MCF7 and T47D cells. These results demonstrate coinheritance with breast cancer of rare alleles that increase activity of ESR1 promoters, and suggest that rare ESR1 regulatory alleles may contribute to inherited predisposition to breast cancer.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"73 1","pages":"e2517736122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351869","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
Spatial gene expression analysis reveals pathological niches in Japanese encephalitis virus neuroinvasion. 空间基因表达分析揭示日本脑炎病毒神经侵袭的病理生态位。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI: 10.1073/pnas.2515006122
Yasuko Orba,Yukie Kashima,Koshiro Tabata,Yukari Itakura,Takuma Ariizumi,William W Hall,Hirofumi Sawa,Yutaka Suzuki,Michihito Sasaki
{"title":"Spatial gene expression analysis reveals pathological niches in Japanese encephalitis virus neuroinvasion.","authors":"Yasuko Orba,Yukie Kashima,Koshiro Tabata,Yukari Itakura,Takuma Ariizumi,William W Hall,Hirofumi Sawa,Yutaka Suzuki,Michihito Sasaki","doi":"10.1073/pnas.2515006122","DOIUrl":"https://doi.org/10.1073/pnas.2515006122","url":null,"abstract":"Japanese encephalitis virus (JEV) infection causes encephalitis in humans and animals. Following intradermal infection, JEV crosses the blood-brain barrier (BBB) and reaches target cells in the brain parenchyma. However, the cellular dynamics and pathological niches involved in JEV neuroinvasion remain poorly understood. In this study, we investigated the early stages of JEV infection in the mouse brain employing a highly multiplexed spatial transcriptomics platform to map viral RNA and host gene expressions in intact brain sections at a single-cell resolution. Although JEV RNA was undetectable in brain sections at 1-day postinfection (dpi), innate immune responses were transiently activated across the brain. At 4 dpi, we detected limited viral RNA and mapped its spatial distribution, identifying glial cells surrounding microvessels as early targets of brain infection. We further characterized transcriptional changes in infected and surrounding bystander cells, revealing cell-type-specific antiviral responses. Notably, JEV neuroinvasion led to the downregulation of endothelial tight junction genes, indicative of an early event that precedes BBB impairment during subsequent disease progression. Our spatial transcriptomic analysis provides insights into cell-type- and region-specific responses to JEV infection, and highlights the early role of glial cells in shaping the immune response landscape of the brain. These findings greatly improve our understanding of JEV pathogenesis before the onset of clinical encephalitis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"105 1","pages":"e2515006122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351871","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
Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3. 细胞内pH调节泛素介导的MAP激酶ERK3的降解。
IF 11.1 1区 综合性期刊
Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-22 DOI: 10.1073/pnas.2501825122
Chloé Tesnière,Fadia Boudghene-Stambouli,Marc Severin,Mallorie Poët,Laure Voisin,Muthulakshmi Ponniah,Mirela Pascariu,Eric Bonneil,Jean-François Trempe,Pierre Thibault,Laurent Counillon,Stine Falsig Pedersen,Sylvain Meloche
{"title":"Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3.","authors":"Chloé Tesnière,Fadia Boudghene-Stambouli,Marc Severin,Mallorie Poët,Laure Voisin,Muthulakshmi Ponniah,Mirela Pascariu,Eric Bonneil,Jean-François Trempe,Pierre Thibault,Laurent Counillon,Stine Falsig Pedersen,Sylvain Meloche","doi":"10.1073/pnas.2501825122","DOIUrl":"https://doi.org/10.1073/pnas.2501825122","url":null,"abstract":"Intracellular pH (pHi) influences diverse cellular processes, including cell proliferation, metabolism, and migration, and is linked to metabolic diseases and cancer. Protonation alters protein charge and conformation, modulating different aspects of protein function. How pHi fluctuations are sensed by signaling proteins and translated into cellular responses remains incompletely understood. Here, we reveal that pHi plays a key role in regulating the stability of the mitogen-activated protein kinase Extracellular signal-regulated kinase 3 (ERK3). Intracellular acidification markedly increases the half-life of ERK3, whereas alkalinization accelerates its degradation. The pH-dependent regulation of ERK3 is rapid, reversible, and consistent across cell types. Mechanistically, we identified a region in the C-terminus of ERK3 that contains pH-sensing motifs. We further show by quantitative proteomics that short-term acidification or alkalinization globally affects the cellular proteome. Our findings underscore the critical role of pHi in ERK3 turnover and suggest a broader role for pH in regulating protein stability and cell signaling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"20 1","pages":"e2501825122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339238","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
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信