eLife最新文献

{"title":"Upregulated expression of ubiquitin ligase TRIM21 promotes PKM2 nuclear translocation and astrocyte activation in experimental autoimmune encephalomyelitis","authors":"Luting Yang, Chunqing Hu, Xiaowen Chen, Jie Zhang, Zhe Feng, Yanxin Xiao, Weitai He, Tingting Cui, Xin Zhang, Yang Yang, Yaling Zhang, Yaping Yan","doi":"https://doi.org/10.7554/elife.98181.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.98181.3","url":null,"abstract":"Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of mice primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-κB and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in mice primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved inference of population histories by integrating genomic and epigenomic data","authors":"Thibaut Sellinger, Frank Johannes, Aurélien Tellier","doi":"https://doi.org/10.7554/elife.89470.4","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.89470.4","url":null,"abstract":"With the availability of high-quality full genome polymorphism (SNPs) data, it becomes feasible to study the past demographic and selective history of populations in exquisite detail. However, such inferences still suffer from a lack of statistical resolution for recent, for example bottlenecks, events, and/or for populations with small nucleotide diversity. Additional heritable (epi)genetic markers, such as indels, transposable elements, microsatellites, or cytosine methylation, may provide further, yet untapped, information on the recent past population history. We extend the Sequential Markovian Coalescent (SMC) framework to jointly use SNPs and other hyper-mutable markers. We are able to (1) improve the accuracy of demographic inference in recent times, (2) uncover past demographic events hidden to SNP-based inference methods, and (3) infer the hyper-mutable marker mutation rates under a finite site model. As a proof of principle, we focus on demographic inference in <i>Arabidopsis thaliana</i> using DNA methylation diversity data from 10 European natural accessions. We demonstrate that segregating single methylated polymorphisms (SMPs) satisfy the modeling assumptions of the SMC framework, while differentially methylated regions (DMRs) are not suitable as their length exceeds that of the genomic distance between two recombination events. Combining SNPs and SMPs while accounting for site- and region-level epimutation processes, we provide new estimates of the glacial age bottleneck and post-glacial population expansion of the European <i>A. thaliana</i> population. Our SMC framework readily accounts for a wide range of heritable genomic markers, thus paving the way for next-generation inference of evolutionary history by combining information from several genetic and epigenetic markers.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysfunction of Calcyphosine-Like gene impairs retinal angiogenesis through the MYC axis and is associated with familial exudative vitreoretinopathy","authors":"Wenjing Liu, Shujin Li, Mu Yang, Jie Ma, Lu Liu, Ping Fei, Qianchun Xiang, Lulin Huang, Peiquan Zhao, Zhenglin Yang, Xianjun Zhu","doi":"https://doi.org/10.7554/elife.96907.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.96907.3","url":null,"abstract":"Familial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants in calcyphosine-like gene (<i>CAPSL</i>) that is associated with FEVR. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell (EC)-specific inactivation of <i>Capsl</i> resulted in delayed radial/vertical vascular progression, compromised endothelial proliferation/migration, recapitulating the human FEVR phenotypes. <i>CAPSL</i>-depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment, and filopodia/lamellipodia formation, as well as disrupted collective cell migration. Transcriptomic and proteomic profiling revealed that <i>CAPSL</i> abolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis of <i>CAPSL</i>-depleted HRECs and <i>c-MYC</i>-depleted human umbilical vein endothelial cells uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, <i>CAPSL</i>, which provides valuable information for genetic counseling of FEVR. This study also reveals that compromised CAPSL function may cause FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-acylation of NLRP3 provides a nigericin sensitive gating mechanism that controls access to the Golgi","authors":"Daniel M Williams, Andrew A Peden","doi":"https://doi.org/10.7554/elife.94302.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.94302.3","url":null,"abstract":"NLRP3 is an inflammasome seeding pattern recognition receptor activated in response to multiple danger signals which perturb intracellular homeostasis. Electrostatic interactions between the NLRP3 polybasic (PB) region and negatively charged lipids on the trans-Golgi network (TGN) have been proposed to recruit NLRP3 to the TGN. In this study, we demonstrate that membrane association of NLRP3 is critically dependant on S-acylation of a highly conserved cysteine residue (Cys-130), which traps NLRP3 in a dynamic S-acylation cycle at the Golgi, and a series of hydrophobic residues preceding Cys-130 which act in conjunction with the PB region to facilitate Cys-130 dependent Golgi enrichment. Due to segregation from Golgi localised thioesterase enzymes caused by a nigericin induced breakdown in Golgi organisation and function, NLRP3 becomes immobilised on the Golgi through reduced de-acylation of its Cys-130 lipid anchor, suggesting that disruptions in Golgi homeostasis are conveyed to NLRP3 through its acylation state. Thus, our work defines a nigericin sensitive S-acylation cycle that gates access of NLRP3 to the Golgi.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine-scale tracking reveals visual field use for predator detection and escape in collective foraging of pigeon flocks","authors":"Mathilde Delacoux, Fumihiro Kano","doi":"https://doi.org/10.7554/elife.95549.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.95549.3","url":null,"abstract":"During collective vigilance, it is commonly assumed that individual animals compromise their feeding time to be vigilant against predators, benefiting the entire group. One notable issue with this assumption concerns the unclear nature of predator ‘detection’, particularly in terms of vision. It remains uncertain how a vigilant individual utilizes its high-acuity vision (such as the fovea) to detect a predator cue and subsequently guide individual and collective escape responses. Using fine-scale motion-capture technologies, we tracked the head and body orientations of pigeons (hence reconstructed their visual fields and foveal projections) foraging in a flock during simulated predator attacks. Pigeons used their fovea to inspect predator cues. Earlier foveation on a predator cue was linked to preceding behaviors related to vigilance and feeding, such as head-up or down positions, head-scanning, and food-pecking. Moreover, earlier foveation predicted earlier evasion flights at both the individual and collective levels. However, we also found that relatively long delay between their foveation and escape responses in individuals obscured the relationship between these two responses. While our results largely support the existing assumptions about vigilance, they also underscore the importance of considering vision and addressing the disparity between detection and escape responses in future research.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental stage shapes the realized energy landscape for a flight specialist","authors":"Elham Nourani, Louise Faure, Hester Brønnvik, Martina Scacco, Enrico Bassi, Wolfgang Fiedler, Martin U Grüebler, Julia S Hatzl, David Jenny, Andrea Roverselli, Petra Sumasgutner, Matthias Tschumi, Martin Wikelski, Kamran Safi","doi":"https://doi.org/10.7554/elife.98818.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.98818.3","url":null,"abstract":"The heterogeneity of the physical environment determines the cost of transport for animals, shaping their energy landscape. Animals respond to this energy landscape by adjusting their distribution and movement to maximize gains and reduce costs. Much of our knowledge about energy landscape dynamics focuses on factors external to the animal, particularly the spatio-temporal variations of the environment. However, an animal’s internal state can significantly impact its ability to perceive and utilize available energy, creating a distinction between the ‘fundamental’ and the ‘realized’ energy landscapes. Here, we show that the realized energy landscape varies along the ontogenetic axis. Locomotor and cognitive capabilities of individuals change over time, especially during the early life stages. We investigate the development of the realized energy landscape in the Central European Alpine population of the golden eagle <i>Aquila chrysaetos</i>, a large predator that requires negotiating the atmospheric environment to achieve energy-efficient soaring flight. We quantified weekly energy landscapes using environmental features for 55 juvenile golden eagles, demonstrating that energetic costs of traversing the landscape decreased with age. Consequently, the potentially flyable area within the Alpine region increased 2170-fold during their first three years of independence. Our work contributes to a predictive understanding of animal movement by presenting ontogeny as a mechanism shaping the realized energy landscape.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Different coexistence patterns between apex carnivores and mesocarnivores based on temporal, spatial, and dietary niche partitioning analysis in Qilian Mountain National Park, China","authors":"Wei Cong, Jia Li, Charlotte Hacker, Ye Li, Yu Zhang, Lixiao Jin, Yi Zhang, Diqiang Li, Yadong Xue, Yuguang Zhang","doi":"https://doi.org/10.7554/elife.90559.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.90559.3","url":null,"abstract":"Carnivores play key roles in maintaining ecosystem structure and function as well as ecological processes. Understanding how sympatric species coexist in natural ecosystems is a central research topic in community ecology and biodiversity conservation. In this study, we explored intra- and interspecific niche partitioning along spatial, temporal, and dietary niche partitioning between apex carnivores (wolf <i>Canis lupus</i>, snow leopard <i>Panthera uncia</i>, Eurasian lynx <i>Lynx lynx</i>) and mesocarnivores (Pallas’s cat <i>Otocolobus manul</i>, red fox <i>Vulpes vulpes</i>, Tibetan fox <i>Vulpes ferrilata</i>) in Qilian Mountain National Park, China, using camera trapping data and DNA metabarcoding sequencing data. Our study showed that apex carnivore species had more overlap temporally (coefficients of interspecific overlap ranging from 0.661 to 0.900) or trophically (Pianka’s index ranging from 0.458 to 0.892), mesocarnivore species had high dietary overlap with each other (Pianka’s index ranging from 0.945 to 0.997), and apex carnivore and mesocarnivore species had high temporal overlap (coefficients of interspecific overlap ranging from 0.497 to 0.855). Large dietary overlap was observed between wolf and snow leopard (Pianka’s index = 0.892) and Pallas’s cat and Tibetan fox (Pianka’s index = 0.997), suggesting the potential for increased resource competition for these species pairs. We concluded that spatial niche partitioning is likely to key driver in facilitating the coexistence of apex carnivore species, while spatial and temporal niche partitioning likely facilitate the coexistence of mesocarnivore species, and spatial and dietary niche partitioning facilitate the coexistence between apex and mesocarnivore species. Our findings consider partitioning across temporal, spatial, and dietary dimensions while examining diverse coexistence patterns of carnivore species in Qilian Mountain National Park, China. These findings will contribute substantially to current understanding of carnivore guilds and effective conservation management in fragile alpine ecosystems.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing a hidden conducting state by manipulating the intracellular domains in KV10.1 exposes the coupling between two gating mechanisms","authors":"Reham Abdelaziz, Adam P Tomczak, Andreas Neef, Luis A Pardo","doi":"https://doi.org/10.7554/elife.91420.4","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.91420.4","url":null,"abstract":"The <i>KCNH</i> family of potassium channels serves relevant physiological functions in both excitable and non-excitable cells, reflected in the massive consequences of mutations or pharmacological manipulation of their function. This group of channels shares structural homology with other voltage-gated K⁺ channels, but the mechanisms of gating in this family show significant differences with respect to the canonical electromechanical coupling in these molecules. In particular, the large intracellular domains of <i>KCNH</i> channels play a crucial role in gating that is still only partly understood. Using <i>KCNH1</i>(K_V10.1) as a model, we have characterized the behavior of a series of modified channels that could not be explained by the current models. With electrophysiological and biochemical methods combined with mathematical modeling, we show that the uncovering of an open state can explain the behavior of the mutants. This open state, which is not detectable in wild-type channels, appears to lack the rapid flicker block of the conventional open state. Because it is accessed from deep closed states, it elucidates intermediate gating events well ahead of channel opening in the wild type. This allowed us to study gating steps prior to opening, which, for example, explain the mechanism of gating inhibition by Ca²⁺-Calmodulin and generate a model that describes the characteristic features of <i>KCNH</i> channels gating.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lateral/caudal ganglionic eminence makes limited contribution to cortical oligodendrocytes","authors":"Jialin Li, Feihong Yang, Yu Tian, Ziwu Wang, Dashi Qi, Zhengang Yang, Jiangang Song, Jing Ding, Xin Wang, Zhuangzhi Zhang","doi":"https://doi.org/10.7554/elife.94317.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.94317.3","url":null,"abstract":"The emergence of myelinating oligodendrocytes represents a pivotal developmental milestone in vertebrates, given their capacity to ensheath axons and facilitate the swift conduction of action potentials. It is widely accepted that cortical oligodendrocyte progenitor cells (OPCs) arise from medial ganglionic eminence (MGE), lateral/caudal ganglionic eminence (LGE/CGE), and cortical radial glial cells (RGCs). Here, we used two different fate mapping strategies to challenge the established notion that the LGE generates cortical OPCs. Furthermore, we used a Cre/loxP-dependent exclusion strategy to reveal that the LGE/CGE does not give rise to cortical OPCs. Additionally, we showed that specifically eliminating MGE-derived OPCs leads to a significant reduction of cortical OPCs. Together, our findings indicate that the LGE does not generate cortical OPCs, contrary to previous beliefs. These findings provide a new view of the developmental origins of cortical OPCs and a valuable foundation for future research on both normal development and oligodendrocyte-related disease.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren’s disease","authors":"Kai-Ting Huang, Larry E Wagner, Takahiro Takano, Xiao-Xuan Lin, Harini Bagavant, Umesh Deshmukh, David I Yule","doi":"https://doi.org/10.7554/elife.97069.3","DOIUrl":"https://doi.org/https://doi.org/10.7554/elife.97069.3","url":null,"abstract":"The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren’s syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca²⁺ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca²⁺ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca²⁺-activated Cl^- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca²⁺. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca²⁺ release channels with TMEM16a, and channel activation was reduced when intracellular Ca²⁺ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca²⁺ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca²⁺ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142185686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}