eLifePub Date : 2024-10-28DOI: 10.7554/eLife.98534
Megan Larmore, Orhi Esarte Palomero, Neha Kamat, Paul G DeCaen
{"title":"A synthetic method to assay polycystin channel biophysics.","authors":"Megan Larmore, Orhi Esarte Palomero, Neha Kamat, Paul G DeCaen","doi":"10.7554/eLife.98534","DOIUrl":"10.7554/eLife.98534","url":null,"abstract":"<p><p>Ion channels are biological transistors that control ionic flux across cell membranes to regulate electrical transmission and signal transduction. They are found in all biological membranes and their conductive state kinetics are frequently disrupted in human diseases. Organelle ion channels are among the most resistant to functional and pharmacological interrogation. Traditional channel protein reconstitution methods rely upon exogenous expression and/or purification from endogenous cellular sources which are frequently contaminated by resident ionophores. Here, we describe a fully synthetic method to assay functional properties of polycystin channels that natively traffic to primary cilia and endoplasmic reticulum organelles. Using this method, we characterize their oligomeric assembly, membrane integration, orientation, and conductance while comparing these results to their endogenous channel properties. Outcomes define a novel synthetic approach that can be applied broadly to investigate channels resistant to biophysical analysis and pharmacological characterization.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11517255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521399","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}
eLifePub Date : 2024-10-28DOI: 10.7554/eLife.103508
Lin Wang, Tak-Sing Wong
{"title":"Tiny particles help insects evade predators.","authors":"Lin Wang, Tak-Sing Wong","doi":"10.7554/eLife.103508","DOIUrl":"10.7554/eLife.103508","url":null,"abstract":"<p><p>By reducing the reflection of ultraviolet light, hollow nanoparticles called brochosomes help to protect leafhoppers from predators.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11517244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497236","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}
eLifePub Date : 2024-10-25DOI: 10.7554/eLife.103292
Valerie Horsley, Aya Nasserdine
{"title":"Don't be so naïve.","authors":"Valerie Horsley, Aya Nasserdine","doi":"10.7554/eLife.103292","DOIUrl":"https://doi.org/10.7554/eLife.103292","url":null,"abstract":"<p><p>New evidence sheds light on actin regulation of pluripotency in human embryonic stem cells.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11509665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497226","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}
{"title":"GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health.","authors":"Dianyuan Zhao, Ziwei Huang, Xiaoyu Li, Huan Wang, Qingwei Hou, Yuyao Wang, Fang Yan, Wenting Yang, Di Liu, Shaoqiong Yi, Chunguang Han, Yanan Hao, Li Tang","doi":"10.7554/eLife.95811","DOIUrl":"https://doi.org/10.7554/eLife.95811","url":null,"abstract":"<p><p>The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of <i>Gdf2</i> (also known as <i>Bmp9</i>) and <i>Bmp10</i> in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. <i>Pdgfb</i> expression was significantly upregulated in KCs and ECs after <i>Gdf2</i> and <i>Bmp10</i> deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from <i>Gdf2/Bmp10</i><sup>HSC-KO</sup> mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11509670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497228","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}
eLifePub Date : 2024-10-25DOI: 10.7554/eLife.84053
Divyoj Singh, Sriram Ramaswamy, Mohit Kumar Jolly, Mohd Suhail Rizvi
{"title":"Emergence of planar cell polarity from the interplay of local interactions and global gradients.","authors":"Divyoj Singh, Sriram Ramaswamy, Mohit Kumar Jolly, Mohd Suhail Rizvi","doi":"10.7554/eLife.84053","DOIUrl":"https://doi.org/10.7554/eLife.84053","url":null,"abstract":"<p><p>Planar cell polarity (PCP) - tissue-scale alignment of the direction of asymmetric localization of proteins at the cell-cell interface - is essential for embryonic development and physiological functions. Abnormalities in PCP can result in developmental imperfections, including neural tube closure defects and misaligned hair follicles. Decoding the mechanisms responsible for PCP establishment and maintenance remains a fundamental open question. While the roles of various molecules - broadly classified into \"global\" and \"local\" modules - have been well-studied, their necessity and sufficiency in explaining PCP and connecting their perturbations to experimentally observed patterns have not been examined. Here, we develop a minimal model that captures the proposed features of PCP establishment - a global tissue-level gradient and local asymmetric distribution of protein complexes. The proposed model suggests that while polarity can emerge without a gradient, the gradient not only acts as a global cue but also increases the robustness of PCP against stochastic perturbations. We also recapitulated and quantified the experimentally observed features of swirling patterns and domineering non-autonomy, using only three free model parameters - the rate of protein binding to membrane, the concentration of PCP proteins, and the gradient steepness. We explain how self-stabilizing asymmetric protein localizations in the presence of tissue-level gradient can lead to robust PCP patterns and reveal minimal design principles for a polarized system.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497227","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}
eLifePub Date : 2024-10-25DOI: 10.7554/eLife.100083
Paul G Kremer, Elizabeth A Lampros, Allison M Blocker, Adam W Barb
{"title":"One N-glycan regulates natural killer cell antibody-dependent cell-mediated cytotoxicity and modulates Fc γ receptor IIIa/CD16a structure.","authors":"Paul G Kremer, Elizabeth A Lampros, Allison M Blocker, Adam W Barb","doi":"10.7554/eLife.100083","DOIUrl":"https://doi.org/10.7554/eLife.100083","url":null,"abstract":"<p><p>Both endogenous antibodies and a subset of antibody therapeutics engage Fc gamma receptor (FcγR)IIIa/CD16a to stimulate a protective immune response. Increasing the FcγRIIIa/IgG1 interaction improves the immune response and thus represents a strategy to improve therapeutic efficacy. FcγRIIIa is a heavily glycosylated receptor and glycan composition affects antibody-binding affinity. Though our laboratory previously demonstrated that natural killer (NK) cell N-glycan composition affected the potency of one key protective mechanism, antibody-dependent cell-mediated cytotoxicity (ADCC), it was unclear if this effect was due to FcγRIIIa glycosylation. Furthermore, the structural mechanism linking glycan composition to affinity and cellular activation remained undescribed. To define the role of individual amino acid and N-glycan residues, we measured affinity using multiple FcγRIIIa glycoforms. We observed stepwise affinity increases with each glycan truncation step, with the most severely truncated glycoform displaying the highest affinity. Removing the N162 glycan demonstrated its predominant role in regulating antibody-binding affinity, in contrast to four other FcγRIIIa N-glycans. We next evaluated the impact of the N162 glycan on NK cell ADCC. NK cells expressing the FcγRIIIa V158 allotype exhibited increased ADCC following kifunensine treatment to limit N-glycan processing. Notably, an increase was not observed with cells expressing the FcγRIIIa V158 S164A variant that lacks N162 glycosylation, indicating that the N162 glycan is required for increased NK cell ADCC. To gain structural insight into the mechanisms of N162 regulation, we applied a novel protein isotope labeling approach in combination with solution NMR spectroscopy. FG loop residues proximal to the N162 glycosylation site showed large chemical shift perturbations following glycan truncation. These data support a model for the regulation of FcγRIIIa affinity and NK cell ADCC whereby composition of the N162 glycan stabilizes the FG loop and thus the antibody-binding site.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11509673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497233","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}
eLifePub Date : 2024-10-25DOI: 10.7554/eLife.104071
Deepali Taneja, Poornima Viswanathan, Sahana V Rajan
{"title":"Navigating neurodiversity in higher education in India.","authors":"Deepali Taneja, Poornima Viswanathan, Sahana V Rajan","doi":"10.7554/eLife.104071","DOIUrl":"https://doi.org/10.7554/eLife.104071","url":null,"abstract":"<p><p>The concept of neurodiversity embraces the idea that there are many different ways of perceiving, thinking about and responding to the world around us. Yet, many countries - including India, with its vast population - still struggle with this concept. Societal perceptions and stereotypes surrounding neurodiversity, often fuelled by ignorance and misinformation, contribute to the marginalisation and exclusion experienced by neurodivergent individuals. This article discusses the challenges and opportunities that neurodivergent students in Indian higher education face, highlighting the urgent need for systemic change to co-create a more inclusive and equitable learning environment.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11509664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497231","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}
{"title":"Actin dynamics switches two distinct modes of endosomal fusion in yolk sac visceral endoderm cells.","authors":"Seiichi Koike, Masashi Tachikawa, Motosuke Tsutsumi, Takuya Okada, Tomomi Nemoto, Kazuko Keino-Masu, Masayuki Masu","doi":"10.7554/eLife.95999","DOIUrl":"10.7554/eLife.95999","url":null,"abstract":"<p><p>Membranes undergo various patterns of deformation during vesicle fusion, but how this membrane deformation is regulated and contributes to fusion remains unknown. In this study, we developed a new method of observing the fusion of individual late endosomes and lysosomes by using mouse yolk sac visceral endoderm cells that have huge endocytic vesicles. We found that there were two distinct fusion modes that were differently regulated. In homotypic fusion, two late endosomes fused quickly, whereas in heterotypic fusion they fused to lysosomes slowly. Mathematical modeling showed that vesicle size is a critical determinant of these fusion types and that membrane fluctuation forces can overcome the vesicle size effects. We found that actin filaments were bound to late endosomes and forces derived from dynamic actin remodeling were necessary for quick fusion during homotypic fusion. Furthermore, cofilin played a role in endocytic fusion by regulating actin turnover. These data suggest that actin promotes vesicle fusion for efficient membrane trafficking in visceral endoderm cells.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11498936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497225","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}
{"title":"DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity.","authors":"Pinhua Wang, Sunayana Sarkar, Menghuan Zhang, Tingting Xiao, Fenhua Kong, Zhe Zhang, Deepa Balasubramanian, Nandan Jayaram, Sayantan Datta, Ruyu He, Ping Wu, Peng Chao, Ying Zhang, Michael Washburn, Laurence A Florens, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Man Mohan","doi":"10.7554/eLife.88318","DOIUrl":"10.7554/eLife.88318","url":null,"abstract":"<p><p>DYRK1A, a ubiquitously expressed kinase<i>,</i> is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of <i>DYRK1A</i> in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the <i>Drosophila</i> neuromuscular junction as a model, we show that the <i>mnb,</i> the fly homologs of <i>DYRK1A</i>, is rescued by RHEB overexpression, suggesting a conserved role of <i>DYRK1A</i> in TORC1 regulation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460807","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}