IF 6.4 1区生物学

eLife Pub Date : 2024-12-27 DOI: 10.7554/eLife.98349

Sam E Benezra, Kripa B Patel, Citlali Perez Campos, Elizabeth M C Hillman, Randy M Bruno

引用次数: 0

Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing. 通过scrna测序揭示化疗诱导的肺腺癌免疫景观重塑和代谢重编程。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-27 DOI: 10.7554/eLife.95988

Yiwei Huang, Gujie Wu, Guoshu Bi, Lin Cheng, Jiaqi Liang, Ming Li, Huan Zhang, Guangyao Shan, Zhengyang Hu, Zhencong Chen, Zongwu Lin, Wei Jiang, Qun Wang, Junjie Xi, Shanye Yin, Cheng Zhan

{"title":"Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing.","authors":"Yiwei Huang, Gujie Wu, Guoshu Bi, Lin Cheng, Jiaqi Liang, Ming Li, Huan Zhang, Guangyao Shan, Zhengyang Hu, Zhencong Chen, Zongwu Lin, Wei Jiang, Qun Wang, Junjie Xi, Shanye Yin, Cheng Zhan","doi":"10.7554/eLife.95988","DOIUrl":"10.7554/eLife.95988","url":null,"abstract":"Chemotherapy is widely used to treat lung adenocarcinoma (LUAD) patients comprehensively. Considering the limitations of chemotherapy due to drug resistance and other issues, it is crucial to explore the impact of chemotherapy and immunotherapy on these aspects. In this study, tumor samples from nine LUAD patients, of which four only received surgery and five received neoadjuvant chemotherapy, were subjected to scRNA-seq analysis. In vitro and in vivo assays, including flow cytometry, immunofluorescence, Seahorse assay, and tumor xenograft models, were carried out to validate our findings. A total of 83,622 cells were enrolled for subsequent analyses. The composition of cell types exhibited high heterogeneity across different groups. Functional enrichment analysis revealed that chemotherapy drove significant metabolic reprogramming in tumor cells and macrophages. We identified two subtypes of macrophages: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG +) and sorted them by flow cytometry. The proportion of Pro-mac cells in LUAD tissues increased significantly after neoadjuvant chemotherapy. Pro-mac cells promote tumor growth and angiogenesis and also suppress tumor immunity. Moreover, by analyzing the remodeling of T and B cells induced by neoadjuvant therapy, we noted that chemotherapy ignited a relatively more robust immune cytotoxic response toward tumor cells. Our study demonstrates that chemotherapy induces metabolic reprogramming within the tumor microenvironment of LUAD, particularly affecting the function and composition of immune cells such as macrophages and T cells. We believe our findings will offer insight into the mechanisms of drug resistance and provide novel therapeutic targets for LUAD in the future.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11677239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Target protein identification in live cells and organisms with a non-diffusive proximity tagging system. 用非扩散接近标记系统鉴定活细胞和生物体中的靶蛋白。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-27 DOI: 10.7554/eLife.102667

Yingjie Sun, Changheng Li, Xiaofei Deng, Wenjie Li, Xiaoyi Deng, Weiqi Ge, Miaoyuan Shi, Ying Guo, Yanxun V Yu, Hai-Bing Zhou, Youngnam N Jin

{"title":"Target protein identification in live cells and organisms with a non-diffusive proximity tagging system.","authors":"Yingjie Sun, Changheng Li, Xiaofei Deng, Wenjie Li, Xiaoyi Deng, Weiqi Ge, Miaoyuan Shi, Ying Guo, Yanxun V Yu, Hai-Bing Zhou, Youngnam N Jin","doi":"10.7554/eLife.102667","DOIUrl":"10.7554/eLife.102667","url":null,"abstract":"Identifying target proteins for bioactive molecules is essential for understanding their mechanisms, developing improved derivatives, and minimizing off-target effects. Despite advances in target identification (target-ID) technologies, significant challenges remain, impeding drug development. Most target-ID methods use cell lysates, but maintaining an intact cellular context is vital for capturing specific drug-protein interactions, such as those with transient protein complexes and membrane-associated proteins. To address these limitations, we developed POST-IT (Pup-On-target for Small molecule Target Identification Technology), a non-diffusive proximity tagging system for live cells, orthogonal to the eukaryotic system. POST-IT utilizes an engineered fusion of proteasomal accessory factor A and HaloTag to transfer Pup to proximal proteins upon directly binding to the small molecule. After significant optimization to eliminate self-pupylation and polypupylation, minimize depupylation, and optimize chemical linkers, POST-IT successfully identified known targets and discovered a new binder, SEPHS2, for dasatinib, and VPS37C as a new target for hydroxychloroquine, enhancing our understanding these drugs' mechanisms of action. Furthermore, we demonstrated the application of POST-IT in live zebrafish embryos, highlighting its potential for broad biological research and drug development.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11677243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Eco-evolutionary dynamics of adapting pathogens and host immunity. 适应病原体和宿主免疫的生态进化动力学。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-27 DOI: 10.7554/eLife.97350

Pierre Barrat-Charlaix, Richard A Neher

{"title":"Eco-evolutionary dynamics of adapting pathogens and host immunity.","authors":"Pierre Barrat-Charlaix, Richard A Neher","doi":"10.7554/eLife.97350","DOIUrl":"10.7554/eLife.97350","url":null,"abstract":"As pathogens spread in a population of hosts, immunity is built up, and the pool of susceptible individuals are depleted. This generates selective pressure, to which many human RNA viruses, such as influenza virus or SARS-CoV-2, respond with rapid antigenic evolution and frequent emergence of immune evasive variants. However, the host's immune systems adapt, and older immune responses wane, such that escape variants only enjoy a growth advantage for a limited time. If variant growth dynamics and reshaping of host-immunity operate on comparable time scales, viral adaptation is determined by eco-evolutionary interactions that are not captured by models of rapid evolution in a fixed environment. Here, we use a Susceptible/Infected model to describe the interaction between an evolving viral population in a dynamic but immunologically diverse host population. We show that depending on strain cross-immunity, heterogeneity of the host population, and durability of immune responses, escape variants initially grow exponentially, but lose their growth advantage before reaching high frequencies. Their subsequent dynamics follows an anomalous random walk determined by future escape variants and results in variant trajectories that are unpredictable. This model can explain the apparent contradiction between the clearly adaptive nature of antigenic evolution and the quasi-neutral dynamics of high-frequency variants observed for influenza viruses.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11677248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A transcription network underlies the dual genomic coordination of mitochondrial biogenesis. 转录网络是线粒体生物发生的双重基因组协调的基础。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-27 DOI: 10.7554/eLife.96536

Fan Zhang, Annie Lee, Anna V Freitas, Jake T Herb, Zong-Heng Wang, Snigdha Gupta, Zhe Chen, Hong Xu

{"title":"A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.","authors":"Fan Zhang, Annie Lee, Anna V Freitas, Jake T Herb, Zong-Heng Wang, Snigdha Gupta, Zhe Chen, Hong Xu","doi":"10.7554/eLife.96536","DOIUrl":"10.7554/eLife.96536","url":null,"abstract":"Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcription factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mitochondrial DNA (mtDNA) deficiency. Among 638 transcription factors annotated in the Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenesis. Additional genetic analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11677238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Passive accumulation of alkaloids in inconspicuously colored frogs refines the evolutionary paradigm of acquired chemical defenses. 生物碱在不显眼的有色青蛙体内的被动积累完善了获得性化学防御的进化范式。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-27 DOI: 10.7554/eLife.100011

Rebecca D Tarvin, Jeffrey L Coleman, David A Donoso, Mileidy Betancourth-Cundar, Karem López-Hervas, Kimberly S Gleason, J Ryan Sanders, Jacqueline M Smith, Santiago R Ron, Juan C Santos, Brian E Sedio, David C Cannatella, Richard W Fitch

{"title":"Passive accumulation of alkaloids in inconspicuously colored frogs refines the evolutionary paradigm of acquired chemical defenses.","authors":"Rebecca D Tarvin, Jeffrey L Coleman, David A Donoso, Mileidy Betancourth-Cundar, Karem López-Hervas, Kimberly S Gleason, J Ryan Sanders, Jacqueline M Smith, Santiago R Ron, Juan C Santos, Brian E Sedio, David C Cannatella, Richard W Fitch","doi":"10.7554/eLife.100011","DOIUrl":"10.7554/eLife.100011","url":null,"abstract":"Understanding the origins of novel, complex phenotypes is a major goal in evolutionary biology. Poison frogs of the family Dendrobatidae have evolved the novel ability to acquire alkaloids from their diet for chemical defense at least three times. However, taxon sampling for alkaloids has been biased towards colorful species, without similar attention paid to inconspicuous ones that are often assumed to be undefended. As a result, our understanding of how chemical defense evolved in this group is incomplete. Here, we provide new data showing that, in contrast to previous studies, species from each undefended poison frog clade have measurable yet low amounts of alkaloids. We confirm that undefended dendrobatids regularly consume mites and ants, which are known sources of alkaloids. Thus, our data suggest that diet is insufficient to explain the defended phenotype. Our data support the existence of a phenotypic intermediate between toxin consumption and sequestration - passive accumulation - that differs from sequestration in that it involves no derived forms of transport and storage mechanisms yet results in low levels of toxin accumulation. We discuss the concept of passive accumulation and its potential role in the origin of chemical defenses in poison frogs and other toxin-sequestering organisms. In light of ideas from pharmacokinetics, we incorporate new and old data from poison frogs into an evolutionary model that could help explain the origins of acquired chemical defenses in animals and provide insight into the molecular processes that govern the fate of ingested toxins.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11677230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A multisite validation of brain white matter pathways of resilience to chronic back pain. 脑白质对慢性背痛恢复能力的多位点验证。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-24 DOI: 10.7554/eLife.96312

Mina Mišić, Noah Lee, Francesca Zidda, Kyungjin Sohn, Katrin Usai, Martin Löffler, Md Nasir Uddin, Arsalan Farooqi, Giovanni Schifitto, Zhengwu Zhang, Frauke Nees, Paul Geha, Herta Flor

{"title":"A multisite validation of brain white matter pathways of resilience to chronic back pain.","authors":"Mina Mišić, Noah Lee, Francesca Zidda, Kyungjin Sohn, Katrin Usai, Martin Löffler, Md Nasir Uddin, Arsalan Farooqi, Giovanni Schifitto, Zhengwu Zhang, Frauke Nees, Paul Geha, Herta Flor","doi":"10.7554/eLife.96312","DOIUrl":"10.7554/eLife.96312","url":null,"abstract":"Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have pointed to brain characteristics as predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over 6- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gasdermin D-mediated neutrophil pyroptosis drives inflammation in psoriasis. 牛皮蛋白d介导的中性粒细胞热亡驱动牛皮癣炎症。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-24 DOI: 10.7554/eLife.101248

Jian Liu, YuYing Jiang, ZiYue Diao, DanDan Chen, RuiYuan Xia, BingWei Wang, Shuo Yang, ZhiQiang Yin

{"title":"Gasdermin D-mediated neutrophil pyroptosis drives inflammation in psoriasis.","authors":"Jian Liu, YuYing Jiang, ZiYue Diao, DanDan Chen, RuiYuan Xia, BingWei Wang, Shuo Yang, ZhiQiang Yin","doi":"10.7554/eLife.101248","DOIUrl":"10.7554/eLife.101248","url":null,"abstract":"Psoriasis is a multifactorial immune-mediated inflammatory disease. Its pathogenesis involves abnormal accumulation of neutrophils and T-cell-related abnormalities. Pyroptosis is a type of regulated cell death associated with innate immunity, but its role in psoriasis is unclear. In this study, we found that gasdermin D (GSDMD) is higher in human psoriatic skin than that in normal skin, and in imiquimod-induced psoriasis-like mouse skin, the expression of Gsdmd was most significantly altered in neutrophils and Il1b was also mainly expressed in neutrophils. Immunohistochemical staining of serial sections of skin lesions from psoriasis patients and healthy control also showed that GSDMD expression is higher in psoriasis lesion, especially in neutrophils. Gsdmd deficiency mitigates psoriasis-like inflammation in mice. GSDMD in neutrophils contributes to psoriasis-like inflammation, while Gsdmd depletion in neutrophils attenuates the development of skin inflammation in psoriasis and reduces the release of the inflammatory cytokines. We found that neutrophil pyroptosis is involved in and contributes to psoriasis inflammation, which provides new insights into the treatment of psoriasis by targeting neutrophil pyroptosis.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Accurate predictions of SARS-CoV-2 infectivity from comprehensive analysis. 从综合分析中准确预测SARS-CoV-2传染性。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-24 DOI: 10.7554/eLife.99833

Jongkeun Park, WonJong Choi, Do Young Seong, Seungpil Jeong, Ju Young Lee, Hyo Jeong Park, Dae Sun Chung, Kijong Yi, Uijin Kim, Ga-Yeon Yoon, Hyeran Kim, Taehoon Kim, Sooyeon Ko, Eun Jeong Min, Hyun-Soo Cho, Nam-Hyuk Cho, Dongwan Hong

{"title":"Accurate predictions of SARS-CoV-2 infectivity from comprehensive analysis.","authors":"Jongkeun Park, WonJong Choi, Do Young Seong, Seungpil Jeong, Ju Young Lee, Hyo Jeong Park, Dae Sun Chung, Kijong Yi, Uijin Kim, Ga-Yeon Yoon, Hyeran Kim, Taehoon Kim, Sooyeon Ko, Eun Jeong Min, Hyun-Soo Cho, Nam-Hyuk Cho, Dongwan Hong","doi":"10.7554/eLife.99833","DOIUrl":"10.7554/eLife.99833","url":null,"abstract":"An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the receptor binding motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in variants of concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 were detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Constitutively active receptor ADGRA3 signaling induces adipose thermogenesis. 组成活性受体ADGRA3信号传导诱导脂肪产热。

IF 6.4 1区生物学

eLife Pub Date : 2024-12-24 DOI: 10.7554/eLife.100205

Zewei Zhao, Longyun Hu, Bigui Song, Tao Jiang, Qian Wu, Jiejing Lin, Xiaoxiao Li, Yi Cai, Jin Li, Bingxiu Qian, Siqi Liu, Jilu Lang, Zhonghan Yang

{"title":"Constitutively active receptor ADGRA3 signaling induces adipose thermogenesis.","authors":"Zewei Zhao, Longyun Hu, Bigui Song, Tao Jiang, Qian Wu, Jiejing Lin, Xiaoxiao Li, Yi Cai, Jin Li, Bingxiu Qian, Siqi Liu, Jilu Lang, Zhonghan Yang","doi":"10.7554/eLife.100205","DOIUrl":"10.7554/eLife.100205","url":null,"abstract":"The induction of adipose thermogenesis plays a critical role in maintaining body temperature and improving metabolic homeostasis to combat obesity. β3-adrenoceptor (β3-AR) is widely recognized as a canonical β-adrenergic G-protein-coupled receptor (GPCR) that plays a crucial role in mediating adipose thermogenesis in mice. Nonetheless, the limited expression of β3-AR in human adipocytes restricts its clinical application. The objective of this study was to identify a GPCR that is highly expressed in human adipocytes and to explore its potential involvement in adipose thermogenesis. Our research findings have demonstrated that the adhesion G-protein-coupled receptor A3 (ADGRA3), an orphan GPCR, plays a significant role in adipose thermogenesis through its constitutively active effects. ADGRA3 exhibited high expression levels in human adipocytes and mouse brown fat. Furthermore, the knockdown of Adgra3 resulted in an exacerbated obese phenotype and a reduction in the expression of thermogenic markers in mice. Conversely, Adgra3 overexpression activated the adipose thermogenic program and improved metabolic homeostasis in mice without exogenous ligand. We found that ADGRA3 facilitates the biogenesis of beige human or mouse adipocytes in vitro. Moreover, hesperetin was identified as a potential agonist of ADGRA3, capable of inducing adipocyte browning and ameliorating insulin resistance in mice. In conclusion, our study demonstrated that the overexpression of constitutively active ADGRA3 or the activation of ADGRA3 by hesperetin can induce adipocyte browning by Gs-PKA-CREB axis. These findings indicate that the utilization of hesperetin and the selective overexpression of ADGRA3 in adipose tissue could serve as promising therapeutic strategies in the fight against obesity.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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