Nucleotide-binding site, leucine-rich repeat (NLR) proteins activate a robust immune response on recognition of pathogen invasion. However, the function and regulatory mechanisms of NLRs during Puccinia striiformis f. sp. tritici (Pst) infection in wheat remain elusive. Here, we identify an ankyrin (ANK) repeat and tetratricopeptide repeat (TPR)-containing protein, TaANK-TPR1, which plays a positive role in the regulation of wheat resistance against Pst and the immune response of NLR. TaANK-TPR1 targets the NLR protein TaRPP13L1 (Recognition of PeronosporaParasitica 13-like 1) to facilitate its homodimerization and cell death to enhance the resistance of wheat against Pst. Meanwhile, TaANK-TPR1 binds to the TGACGT motif (methyl jasmonate-responsive element) of the TaRPP13L1 promoter and activates TaRPP13L1 transcription. Both TaANK-TPR1 and TaRPP13L1 respond to jasmonic acid (JA) signaling via the TGACGT element. Importantly, overexpressing TaRPP13L1 confers robust rust resistance without impacting important agronomic traits in the field. These findings identify a regulatory mechanism of NLR protein and provide targets for improving crop disease resistance.
{"title":"TaANK-TPR1 enhances wheat resistance against stripe rust via controlling gene expression and protein activity of NLR protein TaRPP13L1","authors":"Shuangyuan Guo, Feng Zhang, Xiaoya Du, Xinmei Zhang, Xueling Huang, Zelong Li, Yanqin Zhang, Pengfei Gan, Huankun Li, Min Li, Xinyue Wang, Chunlei Tang, Xiaojie Wang, Zhensheng Kang, Xinmei Zhang","doi":"10.1016/j.devcel.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.017","url":null,"abstract":"Nucleotide-binding site, leucine-rich repeat (NLR) proteins activate a robust immune response on recognition of pathogen invasion. However, the function and regulatory mechanisms of NLRs during <em>Puccinia striiformis</em> f. sp. <em>tritici</em> (<em>Pst</em>) infection in wheat remain elusive. Here, we identify an ankyrin (ANK) repeat and tetratricopeptide repeat (TPR)-containing protein, TaANK-TPR1, which plays a positive role in the regulation of wheat resistance against <em>Pst</em> and the immune response of NLR. TaANK-TPR1 targets the NLR protein TaRPP13L1 (Recognition of <em>Peronospora</em> <em>Parasitica</em> 13-like 1) to facilitate its homodimerization and cell death to enhance the resistance of wheat against <em>Pst</em>. Meanwhile, TaANK-TPR1 binds to the TGACGT motif (methyl jasmonate-responsive element) of the <em>TaRPP13L1</em> promoter and activates <em>TaRPP13L1</em> transcription. Both <em>TaANK-TPR1</em> and <em>TaRPP13L1</em> respond to jasmonic acid (JA) signaling via the TGACGT element. Importantly, overexpressing <em>TaRPP13L1</em> confers robust rust resistance without impacting important agronomic traits in the field. These findings identify a regulatory mechanism of NLR protein and provide targets for improving crop disease resistance.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"61 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417621","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}
Pub Date : 2025-02-13DOI: 10.1016/j.devcel.2025.01.015
Ci Yang, Hong-Xu Li, Hu Gan, Xin Shuai, Chen Dong, Wei Wang, Dandan Lin, Bo Zhong
Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenic mutations are genetic drivers in various cancers, including non-small cell lung cancer (NSCLC). However, the regulatory mechanisms underlying the progression of NSCLC driven by oncogenic KRAS mutants are incompletely understood. Here, we show that ubiquitin specific peptidase 25 (USP25) impedes ring finger protein 31 (RNF31)-mediated linear ubiquitination of KRAS oncogenic mutants (KRASmuts) independently of its deubiquitinase activity, which facilitates the plasma membrane (PM) localization and the downstream oncogenic signaling of KRASmuts. Importantly, knockout (KO) of USP25 effectively suppresses tumor growth and RAS signaling in KRASmuts-driven autochthonous NSCLC mouse models and xenograft models, which is restored by additional deletion or inhibition of RNF31. Notably, knockin of USP25C178A in KRasG12D-driven NSCLC models fails to inhibit cancer progression and reconstitution of USP25C178A into USP25 KO A549 cells restores tumor growth. These findings identify previously uncharacterized roles of USP25 and RNF31 in oncogenic KRAS-driven NSCLC progression and provide potential therapeutic targets for KRASmuts-related cancers.
{"title":"KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31","authors":"Ci Yang, Hong-Xu Li, Hu Gan, Xin Shuai, Chen Dong, Wei Wang, Dandan Lin, Bo Zhong","doi":"10.1016/j.devcel.2025.01.015","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.015","url":null,"abstract":"Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenic mutations are genetic drivers in various cancers, including non-small cell lung cancer (NSCLC). However, the regulatory mechanisms underlying the progression of NSCLC driven by oncogenic KRAS mutants are incompletely understood. Here, we show that ubiquitin specific peptidase 25 (USP25) impedes ring finger protein 31 (RNF31)-mediated linear ubiquitination of KRAS oncogenic mutants (KRAS<sup>muts</sup>) independently of its deubiquitinase activity, which facilitates the plasma membrane (PM) localization and the downstream oncogenic signaling of KRAS<sup>muts</sup>. Importantly, knockout (KO) of USP25 effectively suppresses tumor growth and RAS signaling in KRAS<sup>muts</sup>-driven autochthonous NSCLC mouse models and xenograft models, which is restored by additional deletion or inhibition of RNF31. Notably, knockin of USP25<sup>C178A</sup> in KRas<sup>G12D</sup>-driven NSCLC models fails to inhibit cancer progression and reconstitution of USP25<sup>C178A</sup> into <em>USP25</em> KO A549 cells restores tumor growth. These findings identify previously uncharacterized roles of USP25 and RNF31 in oncogenic KRAS-driven NSCLC progression and provide potential therapeutic targets for KRAS<sup>muts</sup>-related cancers.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"19 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401326","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}
Macrophages possess the capacity to degrade extracellular matrix (ECM), but the specific roles of different cytoskeletal structures in controlling this process are incompletely understood. Here, we report that the inward flow of actin stress fibers delivers endocytosed ECM for lysosomal elimination, replenishing the pool of enzymes for extracellular ECM hydrolysis in actin-rich podosomes. Vimentin deficiency disrupted the balance between stress fibers and podosomes, impairing ECM degradation through integrin CD11b in THP-1 macrophages. In lung adenocarcinoma patient samples, M2-type macrophages exhibit a tighter podosome organization, surrounded by compact vimentin filaments, than M1-type. In vitro experiments verified that the invasion ability of A549 lung carcinoma cells was enhanced when accompanied by wild type, but not vimentin knockout M2-type THP-1, macrophages. Subcutaneous injections of macrophages and tumor cells in nude mice showed that vimentin in macrophages can reduce tumor collagen fibers. Together, our findings provide insights into the cytoskeletal dynamics governing macrophage ECM degradation.
{"title":"Vimentin intermediate filaments coordinate actin stress fibers and podosomes to determine the extracellular matrix degradation by macrophages","authors":"Xinyi Huang, Zhifang Li, Yuhan Huang, Qian Zhang, Yanqin Cui, Xuemeng Shi, Yaming Jiu","doi":"10.1016/j.devcel.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.016","url":null,"abstract":"Macrophages possess the capacity to degrade extracellular matrix (ECM), but the specific roles of different cytoskeletal structures in controlling this process are incompletely understood. Here, we report that the inward flow of actin stress fibers delivers endocytosed ECM for lysosomal elimination, replenishing the pool of enzymes for extracellular ECM hydrolysis in actin-rich podosomes. Vimentin deficiency disrupted the balance between stress fibers and podosomes, impairing ECM degradation through integrin CD11b in THP-1 macrophages. In lung adenocarcinoma patient samples, M2-type macrophages exhibit a tighter podosome organization, surrounded by compact vimentin filaments, than M1-type. <em>In vitro</em> experiments verified that the invasion ability of A549 lung carcinoma cells was enhanced when accompanied by wild type, but not vimentin knockout M2-type THP-1, macrophages. Subcutaneous injections of macrophages and tumor cells in nude mice showed that vimentin in macrophages can reduce tumor collagen fibers. Together, our findings provide insights into the cytoskeletal dynamics governing macrophage ECM degradation.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"15 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401327","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}
Proneural-mesenchymal transition (PMT) is a phenotypic alteration and contributes to the malignant progression of glioblastoma (GBM). Macrophages, as a main infiltrating component of the tumor immune microenvironment (TIM), control the biological processes of PMT; however, the mechanisms driving this process remain largely unknown. Here, the overall landscape of tumor and nontumor cells was described by scMulti-omics technology. Then, we demonstrated that chitinase-3-like protein 1 (CHI3L1) played a critical role in maintaining mesenchymal (MES) status and reprogramming macrophage phenotype using C57BL/6 and NSG mice models derived from PN20 cells. Mechanistically, osteopontin (OPN)/ITGB1 maintained the activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways by establishing a positive feedback loop with the CHI3L1-STAT3 axis, resulting in PMT. CHI3L1 enhanced the phosphorylation, nuclear localization, and transcriptional activity of STAT3 via directly binding its coiled-coil domain (CCD). Importantly, we screened and validated that hygromycin B (HB), an inhibitor of the STAT3-CCD domain, disrupted the CHI3L1-STAT3 interaction, thereby reducing the tumor burden in vitro and in vivo.
{"title":"STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics of glioblastoma","authors":"Wanli Yu, Shikai Gui, Lunshan Peng, Haitao Luo, Jiabao Xie, Juexian Xiao, Yimuran ·Yilamu, Yi Sun, Shihao Cai, Zujue Cheng, Zhennan Tao","doi":"10.1016/j.devcel.2025.01.014","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.014","url":null,"abstract":"Proneural-mesenchymal transition (PMT) is a phenotypic alteration and contributes to the malignant progression of glioblastoma (GBM). Macrophages, as a main infiltrating component of the tumor immune microenvironment (TIM), control the biological processes of PMT; however, the mechanisms driving this process remain largely unknown. Here, the overall landscape of tumor and nontumor cells was described by scMulti-omics technology. Then, we demonstrated that chitinase-3-like protein 1 (CHI3L1) played a critical role in maintaining mesenchymal (MES) status and reprogramming macrophage phenotype using C57BL/6 and NSG mice models derived from PN20 cells. Mechanistically, osteopontin (OPN)/ITGB1 maintained the activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways by establishing a positive feedback loop with the CHI3L1-STAT3 axis, resulting in PMT. CHI3L1 enhanced the phosphorylation, nuclear localization, and transcriptional activity of STAT3 via directly binding its coiled-coil domain (CCD). Importantly, we screened and validated that hygromycin B (HB), an inhibitor of the STAT3-CCD domain, disrupted the CHI3L1-STAT3 interaction, thereby reducing the tumor burden <em>in vitro</em> and <em>in vivo</em>.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"50 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375384","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}
Pub Date : 2025-02-06DOI: 10.1016/j.devcel.2025.01.011
Min Seok Song, Hun Ju Sim, Sung Ho Eun, Min Kyo Jung, Su Jin Hwang, Min Hee Ham, Kihyuck Kwak, Hea Ji Lee, Jin Young Kim, Dong Geon Jang, Hee Chun Chung, Dong Hoon Shin, Ye Jin Kim, Shin Hye Noh, Ji Young Mun, Jae Myun Lee, Min Goo Lee
Cellular stresses, particularly endoplasmic reticulum (ER) stress induced by ER-to-Golgi transport blockade, trigger Golgi-independent secretion of cytosolic and transmembrane proteins. However, the molecular mechanisms underlying this unconventional protein secretion (UPS) remain largely elusive. Here, we report that an ER tubulovesicular structure (ER tubular body [ER-TB]), shaped by the tubular ER-phagy receptors ATL3 and RTN3L, plays an important role in stress-induced UPS of transmembrane proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Correlative light-electron microscopy analyses demonstrate the formation of ER-TB under UPS-inducing conditions in HEK293 and HeLa cells. Individual gene knockdowns of ATL3 and RTN3 inhibit ER-TB formation and the UPS of trafficking-deficient ΔF508-CFTR. Combined supplementation of ATL3 and RTN3L induces ER-TB formation and UPS. ATL3 also participates in the SARS-CoV-2-associated convoluted membrane formation and Golgi-independent trafficking of SARS-CoV-2 spike protein. These findings suggest that ER-TB serves a common function in mediating stress-induced UPS, which participates in various physiological and pathophysiological processes.
{"title":"Tubular ER structures shaped by ER-phagy receptors engage in stress-induced Golgi bypass","authors":"Min Seok Song, Hun Ju Sim, Sung Ho Eun, Min Kyo Jung, Su Jin Hwang, Min Hee Ham, Kihyuck Kwak, Hea Ji Lee, Jin Young Kim, Dong Geon Jang, Hee Chun Chung, Dong Hoon Shin, Ye Jin Kim, Shin Hye Noh, Ji Young Mun, Jae Myun Lee, Min Goo Lee","doi":"10.1016/j.devcel.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.011","url":null,"abstract":"Cellular stresses, particularly endoplasmic reticulum (ER) stress induced by ER-to-Golgi transport blockade, trigger Golgi-independent secretion of cytosolic and transmembrane proteins. However, the molecular mechanisms underlying this unconventional protein secretion (UPS) remain largely elusive. Here, we report that an ER tubulovesicular structure (ER tubular body [ER-TB]), shaped by the tubular ER-phagy receptors ATL3 and RTN3L, plays an important role in stress-induced UPS of transmembrane proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Correlative light-electron microscopy analyses demonstrate the formation of ER-TB under UPS-inducing conditions in HEK293 and HeLa cells. Individual gene knockdowns of ATL3 and RTN3 inhibit ER-TB formation and the UPS of trafficking-deficient ΔF508-CFTR. Combined supplementation of ATL3 and RTN3L induces ER-TB formation and UPS. ATL3 also participates in the SARS-CoV-2-associated convoluted membrane formation and Golgi-independent trafficking of SARS-CoV-2 spike protein. These findings suggest that ER-TB serves a common function in mediating stress-induced UPS, which participates in various physiological and pathophysiological processes.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"55 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192630","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}
Pub Date : 2025-02-05DOI: 10.1016/j.devcel.2025.01.012
Caleb Walker, Aravind Chandrasekaran, Daniel Mansour, Kristin Graham, Andrea Torres, Liping Wang, Eileen M. Lafer, Padmini Rangamani, Jeanne C. Stachowiak
Biomolecular condensates perform diverse physiological functions. Previous work showed that VASP, a processive actin polymerase, forms condensates that assemble and bundle actin. Here, we show that this behavior does not require proteins with specific polymerase activity. Specifically, condensates composed of Lamellipodin, a protein that binds actin but is not an actin polymerase, were also capable of assembling actin filaments. To probe the minimum requirements for condensate-mediated actin bundling, we developed an agent-based computational model. Guided by its predictions, we hypothesized that any condensate-forming protein that binds filamentous actin could bundle filaments through multivalent crosslinking. To test this, we added a filamentous-actin-binding motif to Eps15, a condensate-forming protein that does not normally bind actin. The resulting chimera formed condensates that facilitated efficient assembly and bundling of actin filaments. Collectively, these findings broaden the family of proteins that could organize cytoskeletal filaments to include any filamentous-actin-binding protein that participates in protein condensation.
{"title":"Liquid-like condensates that bind actin promote assembly and bundling of actin filaments","authors":"Caleb Walker, Aravind Chandrasekaran, Daniel Mansour, Kristin Graham, Andrea Torres, Liping Wang, Eileen M. Lafer, Padmini Rangamani, Jeanne C. Stachowiak","doi":"10.1016/j.devcel.2025.01.012","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.012","url":null,"abstract":"Biomolecular condensates perform diverse physiological functions. Previous work showed that VASP, a processive actin polymerase, forms condensates that assemble and bundle actin. Here, we show that this behavior does not require proteins with specific polymerase activity. Specifically, condensates composed of Lamellipodin, a protein that binds actin but is not an actin polymerase, were also capable of assembling actin filaments. To probe the minimum requirements for condensate-mediated actin bundling, we developed an agent-based computational model. Guided by its predictions, we hypothesized that any condensate-forming protein that binds filamentous actin could bundle filaments through multivalent crosslinking. To test this, we added a filamentous-actin-binding motif to Eps15, a condensate-forming protein that does not normally bind actin. The resulting chimera formed condensates that facilitated efficient assembly and bundling of actin filaments. Collectively, these findings broaden the family of proteins that could organize cytoskeletal filaments to include any filamentous-actin-binding protein that participates in protein condensation.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"40 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124316","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}
Pub Date : 2025-02-04DOI: 10.1016/j.devcel.2025.01.008
Sebastian Sorge, Victor Girard, Lena Lampe, Vanessa Tixier, Alexandra Weaver, Theresa Higgins, Alex P. Gould
Diets composed of chemically pure components (holidic diets) are useful for determining the metabolic roles of individual nutrients. For the model organism Drosophila melanogaster, existing holidic diets are unable to support the rapid growth characteristic of the larval stage. Here, we use a nutrient co-optimization strategy across more than 50 diet variants to design a holidic diet for fast development (HolFast), a holidic medium tailored for fast larval growth and development. We identify dietary amino acid ratios optimal for developmental speed but show that they compromise survival unless vitamins and sterols are co-optimized. Rapid development on HolFast is not improved by adding fatty acids, but it is dependent upon their de novo synthesis in the fat body via fatty acid synthase (FASN). HolFast outperforms other holidic diets, supporting rates of growth and development close to those of yeast-based diets and, under germ-free conditions, identical. HolFast has wide applications in nutritional and metabolic studies of Drosophila development.
{"title":"A Drosophila holidic diet optimized for growth and development","authors":"Sebastian Sorge, Victor Girard, Lena Lampe, Vanessa Tixier, Alexandra Weaver, Theresa Higgins, Alex P. Gould","doi":"10.1016/j.devcel.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.008","url":null,"abstract":"Diets composed of chemically pure components (holidic diets) are useful for determining the metabolic roles of individual nutrients. For the model organism <em>Drosophila melanogaster</em>, existing holidic diets are unable to support the rapid growth characteristic of the larval stage. Here, we use a nutrient co-optimization strategy across more than 50 diet variants to design a holidic diet for fast development (HolFast), a holidic medium tailored for fast larval growth and development. We identify dietary amino acid ratios optimal for developmental speed but show that they compromise survival unless vitamins and sterols are co-optimized. Rapid development on HolFast is not improved by adding fatty acids, but it is dependent upon their <em>de novo</em> synthesis in the fat body via fatty acid synthase (<em>FASN</em>). HolFast outperforms other holidic diets, supporting rates of growth and development close to those of yeast-based diets and, under germ-free conditions, identical. HolFast has wide applications in nutritional and metabolic studies of <em>Drosophila</em> development.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"133 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083539","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}
Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt-signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific Usp9x knockout mice exhibit reduced Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we identified β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological mouse models of impaired CNS vascular barrier function, including intracerebral hemorrhage and an oxygen-induced retinopathy, loss of Usp9x intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.
{"title":"Deubiquitinase USP9X controls Wnt signaling for CNS vascular formation and barrier maintenance","authors":"Yi Lei, Jiandong Hu, Jiyun Zhao, Qiangyun Liu, Selena Wei Zhang, Fangfang Wu, Yuming Liu, Honglei Ren, Xiaoyang Qin, Xudong Wu, Fei Gao, Junhao Hu, Kunfu Ouyang, Qiang Liu, Xiangjian Zheng, Lei Shi, Xiaohong Wang","doi":"10.1016/j.devcel.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.009","url":null,"abstract":"Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt-signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific <em>Usp9x</em> knockout mice exhibit reduced Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we identified β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological mouse models of impaired CNS vascular barrier function, including intracerebral hemorrhage and an oxygen-induced retinopathy, loss of <em>Usp9x</em> intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"122 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083540","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}
Pub Date : 2025-02-04DOI: 10.1016/j.devcel.2025.01.010
Jinqiu Li, Yitian Zhou, Ting Shu, Wenqi Lei, Qihao Tang, Yang Yang, Jin Zhang, Wenhui Chen, Bin Zhou, Qinghua Hu, Yanjiang Xing, Jing Wang, Chen Wang
Pulmonary vascular remodeling (PVR), encompassing microvascular loss and muscularization, contributes to multiple respiratory diseases. c-Kit+ cells exhibit differentiation potential into both endothelial cells (ECs) and smooth muscle cells. The potential role of lung c-Kit+ cell differentiation in PVR, however, remains unclear. Lung c-Kit+ cells increase in pulmonary hypertension patients and in the SU5416/hypoxia (SuHx)-induced PVR mouse model. Employing genetic lineage tracing and single-cell RNA sequencing (scRNA-seq), we elucidate that lung-resident c-Kit+ cells display an aerocyte and venular endothelial differentiation in the SuHx model. Ablation of tissue-resident c-Kit+ cells exacerbates PVR. We identify an Nr2f2-expressing c-Kit+ cell subgroup, which exhibitsvenous EC differentiation and increases during PVR. Notably, the elevation of Nr2f2 in c-Kit+ cells via AAV enhances differentiation and mitigates PVR. These findings underscore the protective role of lung tissue-resident c-Kit+ cells in PVR, achieved by differentiating into mature ECs. Targeting NR2F2 expression in c-Kit+ cells emerges as a promising strategy for reversing PVR.
{"title":"Differentiation of lung tissue-resident c-Kit+ cells into microvascular endothelial cells alleviates pulmonary vascular remodeling","authors":"Jinqiu Li, Yitian Zhou, Ting Shu, Wenqi Lei, Qihao Tang, Yang Yang, Jin Zhang, Wenhui Chen, Bin Zhou, Qinghua Hu, Yanjiang Xing, Jing Wang, Chen Wang","doi":"10.1016/j.devcel.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.010","url":null,"abstract":"Pulmonary vascular remodeling (PVR), encompassing microvascular loss and muscularization, contributes to multiple respiratory diseases. c-Kit<sup>+</sup> cells exhibit differentiation potential into both endothelial cells (ECs) and smooth muscle cells. The potential role of lung c-Kit<sup>+</sup> cell differentiation in PVR, however, remains unclear. Lung c-Kit<sup>+</sup> cells increase in pulmonary hypertension patients and in the SU5416/hypoxia (SuHx)-induced PVR mouse model. Employing genetic lineage tracing and single-cell RNA sequencing (scRNA-seq), we elucidate that lung-resident c-Kit<sup>+</sup> cells display an aerocyte and venular endothelial differentiation in the SuHx model. Ablation of tissue-resident c-Kit<sup>+</sup> cells exacerbates PVR. We identify an <em>Nr2f2</em>-expressing c-Kit<sup>+</sup> cell subgroup, which exhibitsvenous EC differentiation and increases during PVR. Notably, the elevation of Nr2f2 in c-Kit<sup>+</sup> cells via AAV enhances differentiation and mitigates PVR. These findings underscore the protective role of lung tissue-resident c-Kit<sup>+</sup> cells in PVR, achieved by differentiating into mature ECs. Targeting NR2F2 expression in c-Kit<sup>+</sup> cells emerges as a promising strategy for reversing PVR.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"61 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083538","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}
Pub Date : 2025-02-03DOI: 10.1016/j.devcel.2024.12.040
Anson Ming Yan Lee, Anne Schreiber
Despite limited translational capacity, senescent cells trigger inflammation by upregulating the translation and secretion of proinflammatory factors. In this issue of Developmental Cell, Kim et al. identify that altered autophagy and SFPQ-dependent EIF4H splicing during senescence redirects translation to promote inflammation, informing therapeutic strategies for cancer and other age-related diseases.
{"title":"Autophagy-dependent changes in alternative splicing bias translation toward inflammation in senescent cells","authors":"Anson Ming Yan Lee, Anne Schreiber","doi":"10.1016/j.devcel.2024.12.040","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.040","url":null,"abstract":"Despite limited translational capacity, senescent cells trigger inflammation by upregulating the translation and secretion of proinflammatory factors. In this issue of <em>Developmental Cell</em>, Kim et al. identify that altered autophagy and SFPQ-dependent <em>EIF4H</em> splicing during senescence redirects translation to promote inflammation, informing therapeutic strategies for cancer and other age-related diseases.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"22 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077204","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}
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