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

{"title":"Single-cell atlas of Leishmania development in sandflies reveals the heterogeneity of transmitted parasites and their role in infection","authors":"Carolina M. C. Catta-Preta, Kashinath Ghosh, David L. Sacks, Tiago R. Ferreira","doi":"10.1073/pnas.2406776121","DOIUrl":"https://doi.org/10.1073/pnas.2406776121","url":null,"abstract":"Sandfly vectors transmit <jats:italic>Leishmania</jats:italic> through egestion of parasites into the host skin. The transmissible dose is shaped by <jats:italic>Leishmania</jats:italic> development in the sandfly gut, described as a sequential differentiation of promastigote morphotypes. Apart from isolated mammal-infective metacyclic promastigotes, little is known about the transcriptional programs and molecular markers for other stages coinhabiting the midgut in mature infections and cotransmitted by the sandfly bite. Here, we elucidate the single-cell transcriptomic complexity of <jats:italic>Leishmania major</jats:italic> colonizing its natural vector <jats:italic>Phlebotomus duboscqi</jats:italic> at early and late infection, providing markers for three transmissible stages. Contrary to prevailing models, our analyses indicate a nonlinear developmental progression, with bifurcation into either replicating early metacyclics or attached and detached haptomonads. We demonstrate that haptomonads constitute a key component of the transmitted inoculum and, along with nondividing late metacyclics, are infectious to and exacerbate the pathology in mice. Our single-cell analysis and validated markers will facilitate further studies on the <jats:italic>Leishmania</jats:italic> life cycle and its implications for vector-to-host transmission dynamics.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"7 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858539","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}

{"title":"Chiral π domain walls composed of twin half-integer surface disclinations in ferroelectric nematic liquid crystals","authors":"Shengzhu Yi, Zening Hong, Zhongjie Ma, Chao Zhou, Miao Jiang, Xiang Huang, Mingjun Huang, Satoshi Aya, Rui Zhang, Qi-Huo Wei","doi":"10.1073/pnas.2413879121","DOIUrl":"https://doi.org/10.1073/pnas.2413879121","url":null,"abstract":"Ferroelectric nematic liquid crystals are polar fluids characterized by microscopic orientational ordering and macroscopic spontaneous polarizations. Within these fluids, domain walls that separate regions of different polarizations are ubiquitous. We demonstrate that the π walls in films of the polar fluids consist of twin half-integer surface disclinations spaced horizontally, enclosing a subdomain where the polarization exhibits left- or right-handed π twists across the film. The degenerate geometric arrangements of the twin disclinations generate kinks and antikinks, parting subdomains of opposite chirality, like the spin-up and spin-down in Ising chains. The hierarchical structures dictate that field-driven polar switching undergo two-step annihilations of the surface disclinations. These findings provide an insight for both comprehending other walls in the polar fluids and domain engineering crucial for advancing their nonlinear and optoelectronic applications.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"13 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858538","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}

{"title":"ACSL4-mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis","authors":"Abhipsa Sinha, Krishan Kumar Saini, Aakash Chandramouli, Kiran Tripathi, Muqtada Ali Khan, Saumya Ranjan Satrusal, Ayushi Verma, Biswajit Mandal, Priyanka Rai, Sanjeev Meena, Mushtaq Ahmad Nengroo, Manish Pratap Singh, Namratha Shashi Bhushan, Madavan Vasudevan, Atin Singhai, Kulranjan Singh, Anand Kumar Mishra, Siddhesh S. Kamat, Dipak Datta","doi":"10.1073/pnas.2408049121","DOIUrl":"https://doi.org/10.1073/pnas.2408049121","url":null,"abstract":"Triple-negative breast cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed to the absence of progesterone receptor. Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyperacetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis, and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"14 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858496","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}

{"title":"Binding site maturation modulated by molecular density underlies Ndc80 binding to kinetochore receptor CENP-T","authors":"Ekaterina V. Tarasovetc, Gunter B. Sissoko, Aleksandr Maiorov, Anna S. Mukhina, Fazoil I. Ataullakhanov, Iain M. Cheeseman, Ekaterina L. Grishchuk","doi":"10.1073/pnas.2401344121","DOIUrl":"https://doi.org/10.1073/pnas.2401344121","url":null,"abstract":"Macromolecular assembly depends on tightly regulated pairwise binding interactions that are selectively favored at assembly sites while being disfavored in the soluble phase. This selective control can arise due to molecular density-enhanced binding, as recently found for the kinetochore scaffold protein CENP-T. When clustered, CENP-T recruits markedly more Ndc80 complexes than its monomeric counterpart, but the underlying molecular basis remains elusive. Here, we use quantitative in vitro assays to reveal two distinct mechanisms driving this behavior. First, Ndc80 binding to CENP-T is a two-step process: initially, Ndc80 molecules rapidly associate and dissociate from disordered N-terminal binding sites on CENP-T. Over time, these sites undergo maturation, resulting in stronger Ndc80 retention. Second, we find that this maturation transition is regulated by a kinetic barrier that is sensitive to the molecular environment. In the soluble phase, binding site maturation is slow, but within CENP-T clusters, this process is markedly accelerated. Notably, the two Ndc80 binding sites in human CENP-T exhibit distinct maturation rates and environmental sensitivities, which correlate with their different amino acid content and predicted binding conformations. This clustering-induced maturation is evident in dividing human cells, suggesting a distinct regulatory entry point for controlling kinetochore assembly. We propose that the tunable acceleration of binding site maturation by molecular crowding may represent a general mechanism for promoting the formation of macromolecular structures.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"31 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858532","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}

{"title":"Mechanism of proton release during water oxidation in Photosystem II","authors":"Friederike Allgöwer, Maximilian C. Pöverlein, A. William Rutherford, Ville R. I. Kaila","doi":"10.1073/pnas.2413396121","DOIUrl":"https://doi.org/10.1073/pnas.2413396121","url":null,"abstract":"Photosystem II (PSII) catalyzes light-driven water oxidation that releases dioxygen into our atmosphere and provides the electrons needed for the synthesis of biomass. The catalysis occurs in the oxygen-evolving oxo-manganese-calcium (Mn <jats:sub>4</jats:sub> O <jats:sub>5</jats:sub> Ca) cluster that drives the oxidation and deprotonation of substrate water molecules leading to the O <jats:sub>2</jats:sub> formation. However, despite recent advances, the mechanism of these reactions remains unclear and much debated. Here, we show that the light-driven Tyr161 <jats:sub>D1</jats:sub> (Y <jats:sub>z</jats:sub> ) oxidation adjacent to the Mn <jats:sub>4</jats:sub> O <jats:sub>5</jats:sub> Ca cluster, decreases the barrier for proton transfer from the putative substrate water molecule (W3/W <jats:sub>x</jats:sub> ) to Glu310 <jats:sub>D2</jats:sub> , accessible to the luminal bulk. By combining hybrid quantum/classical (QM/MM) free energy calculations with atomistic molecular dynamics simulations, we probe the energetics of the proton transfer along the Cl1 pathway. We demonstrate that the proton transfer occurs via water molecules and a cluster of conserved carboxylates, driven by redox-triggered electric fields directed along the pathway. Glu65 <jats:sub>D1</jats:sub> establishes a local molecular gate that controls the proton transfer to the luminal bulk, while Glu312 <jats:sub>D2</jats:sub> acts as a local proton storage site. The identified gating region could be important in preventing backflow of protons to the Mn <jats:sub>4</jats:sub> O <jats:sub>5</jats:sub> Ca cluster. The structural changes, derived here based on the dark-state PSII structure, strongly support recent time-resolved X-ray free electron laser data of the S <jats:sub>3</jats:sub> → S <jats:sub>4</jats:sub> transition (Bhowmick <jats:italic>et al</jats:italic> . Nature 617 , 2023) and reveal the mechanistic basis underlying deprotonation of the substrate water molecules. Our findings provide insight into the water oxidation mechanism of PSII and show how the interplay between redox-triggered electric fields, ion-pairs, and hydration effects control proton transport reactions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"70 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858541","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}

{"title":"Confinement-sensitive volume regulation dynamics via high-speed nuclear morphological measurements","authors":"Yixuan Li, Hui Ting Ong, Hongyue Cui, Xu Gao, Jia Wen Nicole Lee, Yuqi Guo, Rong Li, Fabrizio A. Pennacchio, Paolo Maiuri, Artem K. Efremov, Andrew W. Holle","doi":"10.1073/pnas.2408595121","DOIUrl":"https://doi.org/10.1073/pnas.2408595121","url":null,"abstract":"Diverse tissues in vivo present varying degrees of confinement, constriction, and compression to migrating cells in both homeostasis and disease. The nucleus in particular is subjected to external forces by the physical environment during confined migration. While many systems have been developed to induce nuclear deformation and analyze resultant functional changes, much remains unclear about dynamic volume regulation in confinement due to limitations in time resolution and difficulty imaging in PDMS-based microfluidic chips. Standard volumetric measurement relies on confocal microscopy, which suffers from high phototoxicity, slow speed, limited throughput, and artifacts in fast-moving cells. To address this, we developed a form of double fluorescence exclusion microscopy, designed to function at the interface of microchannel-based PDMS sidewalls, that can track cellular and nuclear volume dynamics during confined migration. By verifying the vertical symmetry of nuclei in confinement, we obtained computational estimates of nuclear surface area. We then tracked nuclear volume and surface area under physiological confinement at a time resolution exceeding 30 frames per minute. We find that during self-induced entrance into confinement, the cell rapidly expands its surface area until a threshold is reached, followed by a rapid decrease in nuclear volume. We next used osmotic shock as a tool to alter nuclear volume in confinement, and found that the nuclear response to hypo-osmotic shock in confinement does not follow classical scaling laws, suggesting that the limited expansion potential of the nuclear envelope might be a constraining factor in nuclear volume regulation in confining environments in vivo.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"31 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858548","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}

{"title":"Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood–retina barrier integrity","authors":"Jessica Furtado, Luiz Henrique Geraldo, Felipe Saceanu Leser, Bartlomiej Bartkowiak, Mathilde Poulet, Hyojin Park, Mark Robinson, Laurence Pibouin-Fragner, Anne Eichmann, Kevin Boyé","doi":"10.1073/pnas.2408674121","DOIUrl":"https://doi.org/10.1073/pnas.2408674121","url":null,"abstract":"The integrity of the blood–retina barrier (BRB) is crucial for phototransduction and vision, by tightly restricting transport of molecules between the blood and surrounding neuronal cells. Breakdown of the BRB leads to the development of retinal diseases. Here, we show that Netrin-1/Unc5b and Norrin/Lrp5 signaling establish a zonated endothelial cell gene expression program that controls BRB integrity. Using single-cell RNA sequencing (scRNA-seq) of postnatal BRB-competent mouse retina endothelial cells (ECs), we identify &gt;100 BRB genes encoding Wnt signaling components, tight junction proteins, and ion and nutrient transporters. We find that BRB gene expression is zonated across arteries, capillaries, and veins and regulated by opposing gradients of the Netrin-1 receptor Unc5b and Lrp5-β-catenin signaling between retinal arterioles and venules. Mice deficient for <jats:italic>Ntn1</jats:italic> or <jats:italic>Unc5b</jats:italic> display more BRB leakage at the arterial end of the vasculature, while <jats:italic>Lrp5</jats:italic> loss of function causes predominantly venular BRB leakage. ScRNA-seq of <jats:italic>Ntn1</jats:italic> and <jats:italic>Unc5b</jats:italic> mutant ECs reveals down-regulated β-catenin signaling and BRB gene expression that is rescued by <jats:italic>Ctnnb1</jats:italic> overactivation, along with BRB integrity. Mechanistically, we demonstrate that Netrin-1 and Norrin additively enhance β-catenin transcriptional activity and Lrp5 phosphorylation via the Discs large homologue 1 (Dlg1) scaffolding protein, and endothelial <jats:italic>Lrp5-Unc5b</jats:italic> function converges in protection of capillary BRB integrity. These findings explain how arteriovenous zonation is established and maintained in the BRB and reveal that BRB gene expression is regulated at the level of endothelial subtypes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"88 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849517","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}

{"title":"Photosynthetic demands on translational machinery drive retention of redundant tRNA metabolism in plant organelles","authors":"Rachael A. DeTar, Joanna M. Chustecki, Ana Martinez-Hottovy, Luis Federico Ceriotti, Amanda K. Broz, Xiaorui Lou, M. Virginia Sanchez-Puerta, Christian Elowsky, Alan C. Christensen, Daniel B. Sloan","doi":"10.1073/pnas.2421485121","DOIUrl":"https://doi.org/10.1073/pnas.2421485121","url":null,"abstract":"Eukaryotic nuclear genomes often encode distinct sets of translation machinery for function in the cytosol vs. organelles (mitochondria and plastids). This raises questions about why multiple translation systems are maintained even though they are capable of comparable functions and whether they evolve differently depending on the compartment where they operate. These questions are particularly interesting in plants because translation machinery, including aminoacyl-transfer RNA (tRNA) synthetases (aaRS), is often dual-targeted to the plastids and mitochondria. These organelles have different functions, with much higher rates of translation in plastids to supply the abundant, rapid-turnover proteins required for photosynthesis. Previous studies have indicated that plant organellar aaRS evolve more slowly compared to mitochondrial aaRS in eukaryotes that lack plastids. Thus, we investigated the evolution of nuclear-encoded organellar and cytosolic aaRS and tRNA maturation enzymes across a broad sampling of angiosperms, including nonphotosynthetic (heterotrophic) plant species with reduced plastid gene expression, to test the hypothesis that translational demands associated with photosynthesis constrain the evolution of enzymes involved in organellar tRNA metabolism. Remarkably, heterotrophic plants exhibited wholesale loss of many organelle-targeted aaRS and other enzymes, even though translation still occurs in their mitochondria and plastids. These losses were often accompanied by apparent retargeting of cytosolic enzymes and tRNAs to the organelles, sometimes preserving aaRS–tRNA charging relationships but other times creating surprising mismatches between cytosolic aaRS and mitochondrial tRNA substrates. Our findings indicate that the presence of a photosynthetic plastid drives the retention of specialized systems for organellar tRNA metabolism.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"54 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849575","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}

{"title":"A frameshift mutation in JAZ10 resolves the growth versus defense dilemma in rice","authors":"Lei-Lei Li, Yujie Xiao, Baohui Wang, Yunqi Zhuang, Yumeng Chen, Jing Lu, Yonggen Lou, Ran Li","doi":"10.1073/pnas.2413564121","DOIUrl":"https://doi.org/10.1073/pnas.2413564121","url":null,"abstract":"CRISPR-Cas9 genome editing systems have revolutionized plant gene functional studies by enabling the targeted introduction of insertion-deletions (INDELs) via the nonhomologous end-joining (NHEJ) pathway. Frameshift-inducing INDELs can introduce a premature termination codon and, in other instances, can lead to the appearance of new proteins. Here, we found that mutations in the rice jasmonate (JA) signaling gene <jats:italic>OsJAZ10</jats:italic> by CRISPR-Cas9-based genome editing did not affect canonical JA signaling. However, a type of mutant with an INDEL that yielded a novel frameshift protein named FJ10 ( <jats:italic> <jats:underline>F</jats:underline> rameshift mutation of <jats:underline>J</jats:underline> AZ <jats:underline>10</jats:underline> </jats:italic> ), exhibited enhanced rice growth and increased resistance to brown planthopper attacks. Overexpression of <jats:italic>FJ10</jats:italic> in wild-type plants phenocopies <jats:italic>OsJAZ10</jats:italic> frameshift mutants. Further characterization revealed that FJ10 interacts with Slender Rice 1 (OsSLR1) and F-box/Kelch 16 (OsFBK16). These interactions disrupt the function of OsSLR1 in suppressing gibberellin-mediated growth and the function of OsFBK16 in repressing lignin-mediated defense responses, respectively. Field experiments with <jats:italic>FJ10</jats:italic> -expressing plants demonstrate that this protein uncouples the growth–defense tradeoff, opening broad avenues to obtain cultivars with enhanced yield without compromised defenses.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849506","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}

{"title":"An antibiotic that mediates immune destruction of senescent cancer cells","authors":"Gabriele Casagrande Raffi, Jian Chen, Xuezhao Feng, Zhen Chen, Cor Lieftink, Shuang Deng, Jinzhe Mo, Chuting Zeng, Marit Steur, Jing Wang, Onno B. Bleijerveld, Liesbeth Hoekman, Nicole van der Wel, Feng Wang, Roderick Beijersbergen, Jian Zheng, Rene Bernards, Liqin Wang","doi":"10.1073/pnas.2417724121","DOIUrl":"https://doi.org/10.1073/pnas.2417724121","url":null,"abstract":"Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell–mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"79 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849509","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}