Pub Date : 2025-07-31DOI: 10.1038/s41422-025-01152-1
Chenxi Cui, Lu Zhao, Ali A. Kermani, Shuzong Du, Tanadet Pipatpolkai, Meiqin Jiang, Sagar Chittori, Yong Zi Tan, Jingyi Shi, Lucie Delemotte, Jianmin Cui, Ji Sun
KCNQ1 potassium channels are essential for physiological processes such as cardiac rhythm and intestinal chloride secretion. KCNE family subunits (KCNE1–5) associate with KCNQ1, conferring distinct properties across various tissues. KCNQ1 activation requires membrane depolarization and phosphatidylinositol 4,5-bisphosphate (PIP2) whose cellular levels are controlled by Gαq-coupled GPCR activation. While modulation of KCNQ1’s voltage-dependent activation by KCNE1/3 is well-characterized, their effects on PIP2-dependent gating of KCNQ1 via GPCR signaling remain less understood. Here we resolved structures of KCNQ1–KCNE1 and reassessed the reported KCNQ1–KCNE3 structures with and without PIP2. We revealed that KCNQ1–KCNE1/3 complexes feature two PIP2-binding sites, with KCNE1/3 contributing to a previously overlooked, uncharacterized site involving residues critical for coupling voltage sensor and pore domains. Via this site, KCNE1 and KCNE3 distinctly modulate the PIP2-dependent gating, in addition to the voltage sensitivity, of KCNQ1. Consequently, KCNE3 converts KCNQ1 into a voltage-insensitive PIP2-gated channel governed by GPCR signaling to maintain ion homeostasis in non-excitable cells. KCNE1, by significantly enhancing KCNQ1’s PIP2 affinity and resistance to GPCR regulation, forms predominantly voltage-gated channels with KCNQ1 for conducting the slow-delayed rectifier current in excitable cardiac cells. Our study highlights how KCNE1/3 modulates KCNQ1 gating in different cellular contexts, providing insights into tissue-specifically targeting multi-functional channels.
{"title":"Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function","authors":"Chenxi Cui, Lu Zhao, Ali A. Kermani, Shuzong Du, Tanadet Pipatpolkai, Meiqin Jiang, Sagar Chittori, Yong Zi Tan, Jingyi Shi, Lucie Delemotte, Jianmin Cui, Ji Sun","doi":"10.1038/s41422-025-01152-1","DOIUrl":"10.1038/s41422-025-01152-1","url":null,"abstract":"KCNQ1 potassium channels are essential for physiological processes such as cardiac rhythm and intestinal chloride secretion. KCNE family subunits (KCNE1–5) associate with KCNQ1, conferring distinct properties across various tissues. KCNQ1 activation requires membrane depolarization and phosphatidylinositol 4,5-bisphosphate (PIP2) whose cellular levels are controlled by Gαq-coupled GPCR activation. While modulation of KCNQ1’s voltage-dependent activation by KCNE1/3 is well-characterized, their effects on PIP2-dependent gating of KCNQ1 via GPCR signaling remain less understood. Here we resolved structures of KCNQ1–KCNE1 and reassessed the reported KCNQ1–KCNE3 structures with and without PIP2. We revealed that KCNQ1–KCNE1/3 complexes feature two PIP2-binding sites, with KCNE1/3 contributing to a previously overlooked, uncharacterized site involving residues critical for coupling voltage sensor and pore domains. Via this site, KCNE1 and KCNE3 distinctly modulate the PIP2-dependent gating, in addition to the voltage sensitivity, of KCNQ1. Consequently, KCNE3 converts KCNQ1 into a voltage-insensitive PIP2-gated channel governed by GPCR signaling to maintain ion homeostasis in non-excitable cells. KCNE1, by significantly enhancing KCNQ1’s PIP2 affinity and resistance to GPCR regulation, forms predominantly voltage-gated channels with KCNQ1 for conducting the slow-delayed rectifier current in excitable cardiac cells. Our study highlights how KCNE1/3 modulates KCNQ1 gating in different cellular contexts, providing insights into tissue-specifically targeting multi-functional channels.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"876-886"},"PeriodicalIF":25.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01152-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759296","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}
Pub Date : 2025-07-23DOI: 10.1038/s41422-025-01158-9
Brian D. Rudd
{"title":"Antibiotics deliver a gut punch to infant immunity","authors":"Brian D. Rudd","doi":"10.1038/s41422-025-01158-9","DOIUrl":"10.1038/s41422-025-01158-9","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"932-933"},"PeriodicalIF":25.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01158-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697749","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}
Pub Date : 2025-07-15DOI: 10.1038/s41422-025-01145-0
Wei Liu, Tao Shi, Chun Lu, Keying Che, Zijian Zhang, Yuting Luo, Daniel Hirschhorn, Hanbing Wang, Shaorui Liu, Yan Wang, Shuang Liu, Haiqiao Sun, Jun Lu, Yuan Liu, Dongquan Shi, Shuai Ding, Heping Xu, Liaoxun Lu, Jianming Xu, Jun Xin, Yinming Liang, Taha Merghoub, Jia Wei, Yan Li
Tumor-infiltrating neutrophils (TINs) are highly heterogeneous and mostly immunosuppressive in the tumor immune microenvironment (TIME). Current biomarkers of TINs and treatment strategies targeting TINs have not yielded optimal responses in patients across cancer types. Here, we separated human and mouse neutrophils into three developmental stages, including promyelocyte (PM), myelocyte & metamyelocyte (MC & MM), and band & segmented (BD & SC) neutrophils. Based on this separation, we observed the predominance of human but not mouse MC & MM-stage neutrophils in bone marrow (BM), which exhibit potent immunosuppressive and tumor-promoting properties. MCs & MMs also occupy the majority of TINs among patients with 17 cancer types. Moreover, through the creation of a NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt (NCG)-Gfi1−/− human immune system (HIS) mouse model, which supports efficient reconstitution of human TIN, we found a significant increase of BM MCs & MMs in tumor-bearing mice. By comparing the single-cell RNA sequencing analysis results of human neutrophils from both BM and tumors, we found that CD63 and Galectin-3 distinguish MC & MM from neutrophil populations in cancer patients. Furthermore, we proposed a strategy with Fms-like tyrosine kinase 3 ligand to specifically induce the trans-differentiation of MCs & MMs into monocytic cells, and trigger tumor control in NCG-Gfi1−/− HIS mice. Thus, our findings establish an essential role of human MC & MM-stage neutrophils in promoting cancer progression, and suggest their potential as targets for developing potential biomarkers and immunotherapies for cancer.
{"title":"Human myelocyte and metamyelocyte-stage neutrophils suppress tumor immunity and promote cancer progression","authors":"Wei Liu, Tao Shi, Chun Lu, Keying Che, Zijian Zhang, Yuting Luo, Daniel Hirschhorn, Hanbing Wang, Shaorui Liu, Yan Wang, Shuang Liu, Haiqiao Sun, Jun Lu, Yuan Liu, Dongquan Shi, Shuai Ding, Heping Xu, Liaoxun Lu, Jianming Xu, Jun Xin, Yinming Liang, Taha Merghoub, Jia Wei, Yan Li","doi":"10.1038/s41422-025-01145-0","DOIUrl":"10.1038/s41422-025-01145-0","url":null,"abstract":"Tumor-infiltrating neutrophils (TINs) are highly heterogeneous and mostly immunosuppressive in the tumor immune microenvironment (TIME). Current biomarkers of TINs and treatment strategies targeting TINs have not yielded optimal responses in patients across cancer types. Here, we separated human and mouse neutrophils into three developmental stages, including promyelocyte (PM), myelocyte & metamyelocyte (MC & MM), and band & segmented (BD & SC) neutrophils. Based on this separation, we observed the predominance of human but not mouse MC & MM-stage neutrophils in bone marrow (BM), which exhibit potent immunosuppressive and tumor-promoting properties. MCs & MMs also occupy the majority of TINs among patients with 17 cancer types. Moreover, through the creation of a NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt (NCG)-Gfi1−/− human immune system (HIS) mouse model, which supports efficient reconstitution of human TIN, we found a significant increase of BM MCs & MMs in tumor-bearing mice. By comparing the single-cell RNA sequencing analysis results of human neutrophils from both BM and tumors, we found that CD63 and Galectin-3 distinguish MC & MM from neutrophil populations in cancer patients. Furthermore, we proposed a strategy with Fms-like tyrosine kinase 3 ligand to specifically induce the trans-differentiation of MCs & MMs into monocytic cells, and trigger tumor control in NCG-Gfi1−/− HIS mice. Thus, our findings establish an essential role of human MC & MM-stage neutrophils in promoting cancer progression, and suggest their potential as targets for developing potential biomarkers and immunotherapies for cancer.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 8","pages":"588-606"},"PeriodicalIF":25.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629697","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 : 2025-07-15DOI: 10.1038/s41422-025-01148-x
Maximilian Fliegauf, Marco Prinz
{"title":"Too sweet to be savory: how fructose elicits microglia-driven disturbance of neurodevelopment","authors":"Maximilian Fliegauf, Marco Prinz","doi":"10.1038/s41422-025-01148-x","DOIUrl":"10.1038/s41422-025-01148-x","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"930-931"},"PeriodicalIF":25.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01148-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629696","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}
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