Pub Date : 2025-11-13DOI: 10.1038/s41422-025-01194-5
Li Chen, Xia Bu, Yishuang Sun, Daoyuan Huang, Yong Chen, Tao Hou, Xiaoping Hu, Jingchao Wang, Peiqiang Yan, Yihang Qi, Weiwei Jiang, Yan Xiong, Jing Liu, Yang Gao, Mengxi Huan, Bin Wang, Qianjia Liu, Xiaoming Dai, Fabin Dang, John M. Asara, Masanori Fujimoto, Hiroyuki Inuzuka, Jian Jin, Jinfang Zhang, Gordon J. Freeman, Wenyi Wei
Immune checkpoints serve as regulatory pathways that are essential for regulating immune response and homeostasis. As such, many components along the pathway have emerged as pivotal targets in cancer therapy. To overcome the treatment resistance and limited efficacy encountered by current immune checkpoint therapies, there is an urgent need for new immunotherapeutic targets and strategies. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint protein with a unique expression pattern and has emerged as a novel therapeutic target in anti-tumor immunotherapy; however, the precise role of VISTA and its regulatory mechanisms in tumor cells remain incompletely understood. Here, we identify a novel strategy targeting VISTA for cancer immunotherapy, enhancing therapeutic outcomes. Mechanistically, we show that VISTA undergoes anaphase-promoting complex/cyclosome (APC/C)/CDH1-mediated ubiquitination and subsequent proteasomal degradation, a process that can be reversed by the deubiquitinase USP2. Therapeutically, the USP2 inhibitor MS102 significantly reduces VISTA protein abundance in vitro and in vivo, enhances T cell responses, and synergizes with anti-PD-1 immunotherapy to improve survival in syngeneic mouse tumor models. Our findings reveal a regulatory network for VISTA stability control and support the combination of USP2 inhibitors with anti-PD-1 immunotherapy to enhance anti-tumor immune responses.
免疫检查点是调节免疫反应和体内平衡的重要途径。因此，该通路上的许多成分已成为癌症治疗的关键靶点。为了克服目前免疫检查点疗法所遇到的治疗耐药性和有限的疗效，迫切需要新的免疫治疗靶点和策略。V-domain Ig suppressor of T cell activation （VISTA）是一种具有独特表达模式的免疫检查点蛋白，已成为抗肿瘤免疫治疗的新靶点；然而，VISTA在肿瘤细胞中的确切作用及其调控机制尚不完全清楚。在这里，我们确定了一种针对VISTA的癌症免疫治疗新策略，提高了治疗效果。在机制上，我们发现VISTA经历了后期促进复合物/环体(APC/C)/ cdh1介导的泛素化和随后的蛋白酶体降解，这一过程可以通过去泛素酶USP2逆转。在治疗上，USP2抑制剂MS102在体外和体内显著降低VISTA蛋白丰度，增强T细胞反应，并与抗pd -1免疫疗法协同作用，提高同基因小鼠肿瘤模型的生存率。我们的研究结果揭示了VISTA稳定性控制的调控网络，并支持USP2抑制剂与抗pd -1免疫疗法联合使用以增强抗肿瘤免疫应答。
{"title":"Targeted destruction of VISTA boosts anti-tumor immunotherapy","authors":"Li Chen, Xia Bu, Yishuang Sun, Daoyuan Huang, Yong Chen, Tao Hou, Xiaoping Hu, Jingchao Wang, Peiqiang Yan, Yihang Qi, Weiwei Jiang, Yan Xiong, Jing Liu, Yang Gao, Mengxi Huan, Bin Wang, Qianjia Liu, Xiaoming Dai, Fabin Dang, John M. Asara, Masanori Fujimoto, Hiroyuki Inuzuka, Jian Jin, Jinfang Zhang, Gordon J. Freeman, Wenyi Wei","doi":"10.1038/s41422-025-01194-5","DOIUrl":"10.1038/s41422-025-01194-5","url":null,"abstract":"Immune checkpoints serve as regulatory pathways that are essential for regulating immune response and homeostasis. As such, many components along the pathway have emerged as pivotal targets in cancer therapy. To overcome the treatment resistance and limited efficacy encountered by current immune checkpoint therapies, there is an urgent need for new immunotherapeutic targets and strategies. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint protein with a unique expression pattern and has emerged as a novel therapeutic target in anti-tumor immunotherapy; however, the precise role of VISTA and its regulatory mechanisms in tumor cells remain incompletely understood. Here, we identify a novel strategy targeting VISTA for cancer immunotherapy, enhancing therapeutic outcomes. Mechanistically, we show that VISTA undergoes anaphase-promoting complex/cyclosome (APC/C)/CDH1-mediated ubiquitination and subsequent proteasomal degradation, a process that can be reversed by the deubiquitinase USP2. Therapeutically, the USP2 inhibitor MS102 significantly reduces VISTA protein abundance in vitro and in vivo, enhances T cell responses, and synergizes with anti-PD-1 immunotherapy to improve survival in syngeneic mouse tumor models. Our findings reveal a regulatory network for VISTA stability control and support the combination of USP2 inhibitors with anti-PD-1 immunotherapy to enhance anti-tumor immune responses.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"987-1002"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499485","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 : 2025-11-11DOI: 10.1038/s41422-025-01192-7
Sara Marchese, Andrea Mattevi
{"title":"Myeloperoxidase: one enzyme, two jobs.","authors":"Sara Marchese, Andrea Mattevi","doi":"10.1038/s41422-025-01192-7","DOIUrl":"https://doi.org/10.1038/s41422-025-01192-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494753","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 : 2025-11-07DOI: 10.1038/s41422-025-01191-8
Huibing Zhang, Xueting Wang, Kun Xi, Qingya Shen, Jianheng Xue, Yanqing Zhu, Shao-Kun Zang, Tianqiang Yu, Dan-Dan Shen, Jia Guo, Li-Nan Chen, Su-Yu Ji, Jiao Qin, Yingjun Dong, Mingming Zhao, Ming Yang, Haijing Wu, Guoli Yang, Yan Zhang
Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with Gz and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR–Gz and μOR–βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the Gi-, Gz-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the Gi-, Gz-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.
{"title":"The molecular basis of μ-opioid receptor signaling plasticity","authors":"Huibing Zhang, Xueting Wang, Kun Xi, Qingya Shen, Jianheng Xue, Yanqing Zhu, Shao-Kun Zang, Tianqiang Yu, Dan-Dan Shen, Jia Guo, Li-Nan Chen, Su-Yu Ji, Jiao Qin, Yingjun Dong, Mingming Zhao, Ming Yang, Haijing Wu, Guoli Yang, Yan Zhang","doi":"10.1038/s41422-025-01191-8","DOIUrl":"10.1038/s41422-025-01191-8","url":null,"abstract":"Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with Gz and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR–Gz and μOR–βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the Gi-, Gz-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the Gi-, Gz-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1021-1036"},"PeriodicalIF":25.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01191-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457272","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 : 2025-10-23DOI: 10.1038/s41422-025-01189-2
Alicia De La Cruz, H. Peter Larsson
{"title":"KCNQ1 and PIP2: it takes two to tango","authors":"Alicia De La Cruz, H. Peter Larsson","doi":"10.1038/s41422-025-01189-2","DOIUrl":"10.1038/s41422-025-01189-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"922-923"},"PeriodicalIF":25.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01189-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351546","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 : 2025-10-14DOI: 10.1038/s41422-025-01171-y
Titus Schlüter, Yuri van Elsas, Bram Priem, Athanasios Ziogas, Mihai G. Netea
The innate immune system adapts its behavior based on previous insults, mounting an enhanced response upon re-exposure. Hematopoietic progenitors in the bone marrow and peripheral innate immune cells can undergo epigenetic and metabolic reprogramming, establishing an innate immune memory known as trained immunity. The concept of trained immunity recently gained relevance in our understanding of how innate immunity is regulated in various diseases. This review explores the role of trained immunity in infections, autoimmune disease, cardiovascular disease, cancer, and neurodegenerative disease. We discuss how trained immunity can provide heterologous protection against infections, as it has been induced for decades by the Bacillus Calmette Guérin vaccine, how it can help counteract immunosuppression, and how it can be inappropriately induced leading to chronic inflammation. By understanding how trained immunity is involved in processes leading to health and disease, novel therapeutic strategies can be developed.
{"title":"Trained immunity: induction of an inflammatory memory in disease","authors":"Titus Schlüter, Yuri van Elsas, Bram Priem, Athanasios Ziogas, Mihai G. Netea","doi":"10.1038/s41422-025-01171-y","DOIUrl":"10.1038/s41422-025-01171-y","url":null,"abstract":"The innate immune system adapts its behavior based on previous insults, mounting an enhanced response upon re-exposure. Hematopoietic progenitors in the bone marrow and peripheral innate immune cells can undergo epigenetic and metabolic reprogramming, establishing an innate immune memory known as trained immunity. The concept of trained immunity recently gained relevance in our understanding of how innate immunity is regulated in various diseases. This review explores the role of trained immunity in infections, autoimmune disease, cardiovascular disease, cancer, and neurodegenerative disease. We discuss how trained immunity can provide heterologous protection against infections, as it has been induced for decades by the Bacillus Calmette Guérin vaccine, how it can help counteract immunosuppression, and how it can be inappropriately induced leading to chronic inflammation. By understanding how trained immunity is involved in processes leading to health and disease, novel therapeutic strategies can be developed.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"792-802"},"PeriodicalIF":25.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01171-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283189","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}
The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (IKs) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5–3.4 Å) structures of human KCNQ1APO, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4–S5 linker, maintaining a loop conformation during IKs gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during IKs gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4–S5 linker, KCNE1, and the adjacent S6’, stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes IKs function and provides a foundation for developing targeted LQTS therapy.
{"title":"Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating","authors":"Ling Zhong, Xiaoqing Lin, Xinyu Cheng, Shuangyan Wan, Yaoguang Hua, Weiwei Nan, Bin Hu, Xiangjun Peng, Zihan Zhou, Qiansen Zhang, Huaiyu Yang, Frank Noé, Zhenzhen Yan, Dexiang Jiang, Hangyu Zhang, Fengjiao Liu, Chenxin Xiao, Zhuo Zhou, Yimin Mou, Haijie Yu, Lijuan Ma, Chen Huang, Vincent Kam Wai Wong, Sookja Kim Chung, Bing Shen, Zhi-Hong Jiang, Erwin Neher, Wandi Zhu, Jin Zhang, Panpan Hou","doi":"10.1038/s41422-025-01182-9","DOIUrl":"10.1038/s41422-025-01182-9","url":null,"abstract":"The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (IKs) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5–3.4 Å) structures of human KCNQ1APO, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4–S5 linker, maintaining a loop conformation during IKs gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during IKs gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4–S5 linker, KCNE1, and the adjacent S6’, stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes IKs function and provides a foundation for developing targeted LQTS therapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"887-899"},"PeriodicalIF":25.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01182-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205680","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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