{"title":"DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells.","authors":"Jeremy Rich, Melanie Bennaroch, Laura Notel, Polina Patalakh, Julien Alberola, Fayez Issa, Paule Opolon, Olivia Bawa, Windy Rondof, Antonin Marchais, Philippe Dessen, Guillaume Meurice, Morgane Le-Gall, Melanie Polrot, Karine Ser-Le Roux, Kamel Mamchaoui, Nathalie Droin, Hana Raslova, Pascal Maire, Birgit Geoerger, Iryna Pirozhkova","doi":"10.1038/s44321-024-00097-z","DOIUrl":"10.1038/s44321-024-00097-z","url":null,"abstract":"<p><p>We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1840-1885"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-02DOI: 10.1038/s44321-024-00094-2
Yifan Tai, Angela Chow, Seoyoung Han, Courtney Coker, Wanchao Ma, Yifan Gu, Valeria Estrada Navarro, Manoj Kandpal, Hanina Hibshoosh, Kevin Kalinsky, Katia Manova-Todorova, Anton Safonov, Elaine M Walsh, Mark Robson, Larry Norton, Richard Baer, Taha Merghoub, Anup K Biswas, Swarnali Acharyya
{"title":"FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer.","authors":"Yifan Tai, Angela Chow, Seoyoung Han, Courtney Coker, Wanchao Ma, Yifan Gu, Valeria Estrada Navarro, Manoj Kandpal, Hanina Hibshoosh, Kevin Kalinsky, Katia Manova-Todorova, Anton Safonov, Elaine M Walsh, Mark Robson, Larry Norton, Richard Baer, Taha Merghoub, Anup K Biswas, Swarnali Acharyya","doi":"10.1038/s44321-024-00094-2","DOIUrl":"10.1038/s44321-024-00094-2","url":null,"abstract":"<p><p>Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8<sup>+</sup> T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1957-1980"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-08DOI: 10.1038/s44321-024-00096-0
Alexander Seidinger, Richard Roberts, Yan Bai, Marion Müller, Eva Pfeil, Michaela Matthey, Sarah Rieck, Judith Alenfelder, Gabriele M König, Alexander Pfeifer, Evi Kostenis, Anna Klinke, Bernd K Fleischmann, Daniela Wenzel
{"title":"Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension.","authors":"Alexander Seidinger, Richard Roberts, Yan Bai, Marion Müller, Eva Pfeil, Michaela Matthey, Sarah Rieck, Judith Alenfelder, Gabriele M König, Alexander Pfeifer, Evi Kostenis, Anna Klinke, Bernd K Fleischmann, Daniela Wenzel","doi":"10.1038/s44321-024-00096-0","DOIUrl":"10.1038/s44321-024-00096-0","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1930-1956"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-19DOI: 10.1038/s44321-024-00106-1
Jing Wang, Qiyao Chai, Zehui Lei, Yiru Wang, Jiehua He, Pupu Ge, Zhe Lu, Lihua Qiang, Dongdong Zhao, Shanshan Yu, Changgen Qiu, Yanzhao Zhong, Bing-Xi Li, Lingqiang Zhang, Yu Pang, George Fu Gao, Cui Hua Liu
{"title":"LILRB1-HLA-G axis defines a checkpoint driving natural killer cell exhaustion in tuberculosis.","authors":"Jing Wang, Qiyao Chai, Zehui Lei, Yiru Wang, Jiehua He, Pupu Ge, Zhe Lu, Lihua Qiang, Dongdong Zhao, Shanshan Yu, Changgen Qiu, Yanzhao Zhong, Bing-Xi Li, Lingqiang Zhang, Yu Pang, George Fu Gao, Cui Hua Liu","doi":"10.1038/s44321-024-00106-1","DOIUrl":"10.1038/s44321-024-00106-1","url":null,"abstract":"<p><p>Chronic infections, including Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), can induce host immune exhaustion. However, the key checkpoint molecules involved in this process and the underlying regulatory mechanisms remain largely undefined, which impede the application of checkpoint-based immunotherapy in infectious diseases. Here, through adopting time-of-flight mass cytometry and transcriptional profiling to systematically analyze natural killer (NK) cell surface receptors, we identify leukocyte immunoglobulin like receptor B1 (LILRB1) as a critical checkpoint receptor that defines a TB-associated cell subset (LILRB1<sup>+</sup> NK cells) and drives NK cell exhaustion in TB. Mechanistically, Mtb-infected macrophages display high expression of human leukocyte antigen-G (HLA-G), which upregulates and activates LILRB1 on NK cells to impair their functions by inhibiting mitogen-activated protein kinase (MAPK) signaling via tyrosine phosphatases SHP1/2. Furthermore, LILRB1 blockade restores NK cell-dependent anti-Mtb immunity in immuno-humanized mice. Thus, LILRB1-HLA-G axis constitutes a NK cell immune checkpoint in TB and serves as a promising immunotherapy target.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1755-1790"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-15DOI: 10.1038/s44321-024-00100-7
Yao Zhang, Christina Lee, Shuo Geng, Jing Wang, Udipta Bohara, Jacqueline Hou, Ziyue Yi, Liwu Li
{"title":"Immune-enhancing neutrophils reprogrammed by subclinical low-dose endotoxin in cancer treatment.","authors":"Yao Zhang, Christina Lee, Shuo Geng, Jing Wang, Udipta Bohara, Jacqueline Hou, Ziyue Yi, Liwu Li","doi":"10.1038/s44321-024-00100-7","DOIUrl":"10.1038/s44321-024-00100-7","url":null,"abstract":"<p><p>Despite the re-emergence of the pioneering \"Coley's toxin\" concept in anti-cancer immune therapies highlighted by check-point inhibitors and CAR-T approaches, fundamental mechanisms responsible for the immune-enhancing efficacy of low-dose \"Coley's toxin\" remain poorly understood. This study examines the novel reprogramming of immune-enhancing neutrophils by super-low dose endotoxin conducive for anti-cancer therapies. Through integrated analyses including scRNAseq and functional characterizations, we examined the efficacy of reprogrammed neutrophils in treating experimental cancer. We observed that neutrophils trained by super-low dose endotoxin adopt a potent immune-enhancing phenotype characterized by CD177<sup>lo</sup>CD11b<sup>lo</sup>CD80<sup>hi</sup>CD40<sup>hi</sup>Dectin2<sup>hi</sup>. Both murine and human neutrophils trained by super-low dose endotoxin exhibit relieved suppression of adaptive T cells as compared to un-trained neutrophils. Functionally, neutrophils trained by super-low dose endotoxin can potently reduce tumor burden when transfused into recipient tumor-bearing mice. Mechanistically, Super-low dose endotoxin enables the generation of immune-enhancing neutrophils through activating STAT5 and reducing innate suppressor IRAK-M. Together, our data clarify the long-held mystery of \"Coley's toxin\" in rejuvenating anti-tumor immune defense, and provide a proof-of-concept in developing innate neutrophil-based anti-tumor therapeutics.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1886-1900"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-19DOI: 10.1038/s44321-024-00098-y
Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, David Escors
{"title":"PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.","authors":"Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, David Escors","doi":"10.1038/s44321-024-00098-y","DOIUrl":"10.1038/s44321-024-00098-y","url":null,"abstract":"<p><p>Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1791-1816"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-15DOI: 10.1038/s44321-024-00103-4
Xingjuan Chen, Yunzheng Yan, Zhiqiang Liu, Shaokang Yang, Wei Li, Zhuang Wang, Mengyuan Wang, Juan Guo, Zhenyang Li, Weiyan Zhu, Jingjing Yang, Jiye Yin, Qingsong Dai, Yuexiang Li, Cui Wang, Lei Zhao, Xiaotong Yang, Xiaojia Guo, Ling Leng, Jiaxi Xu, Alexander G Obukhov, Ruiyuan Cao, Wu Zhong
{"title":"In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection.","authors":"Xingjuan Chen, Yunzheng Yan, Zhiqiang Liu, Shaokang Yang, Wei Li, Zhuang Wang, Mengyuan Wang, Juan Guo, Zhenyang Li, Weiyan Zhu, Jingjing Yang, Jiye Yin, Qingsong Dai, Yuexiang Li, Cui Wang, Lei Zhao, Xiaotong Yang, Xiaojia Guo, Ling Leng, Jiaxi Xu, Alexander G Obukhov, Ruiyuan Cao, Wu Zhong","doi":"10.1038/s44321-024-00103-4","DOIUrl":"10.1038/s44321-024-00103-4","url":null,"abstract":"<p><p>Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1817-1839"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-08-01Epub Date: 2024-07-08DOI: 10.1038/s44321-024-00093-3
Ibrahim Hawwari, Lukas Rossnagel, Nathalia Rosero, Salie Maasewerd, Matilde B Vasconcelos, Marius Jentzsch, Agnieszka Demczuk, Lino L Teichmann, Lisa Meffert, Damien Bertheloot, Lucas S Ribeiro, Sebastian Kallabis, Felix Meissner, Moshe Arditi, Asli E Atici, Magali Noval Rivas, Bernardo S Franklin
{"title":"Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes.","authors":"Ibrahim Hawwari, Lukas Rossnagel, Nathalia Rosero, Salie Maasewerd, Matilde B Vasconcelos, Marius Jentzsch, Agnieszka Demczuk, Lino L Teichmann, Lisa Meffert, Damien Bertheloot, Lucas S Ribeiro, Sebastian Kallabis, Felix Meissner, Moshe Arditi, Asli E Atici, Magali Noval Rivas, Bernardo S Franklin","doi":"10.1038/s44321-024-00093-3","DOIUrl":"10.1038/s44321-024-00093-3","url":null,"abstract":"<p><p>In humans, blood Classical CD14<sup>+</sup> monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1901-1929"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alice Gambelli, Anna Nespolo, Gian Luca Rampioni Vinciguerra, Eliana Pivetta, Ilenia Pellarin, Milena S Nicoloso, Chiara Scapin, Linda Stefenatti, Ilenia Segatto, Andrea Favero, Sara D'Andrea, Maria Teresa Mucignat, Michele Bartoletti, Emilio Lucia, Monica Schiappacassi, Paola Spessotto, Vincenzo Canzonieri, Giorgio Giorda, Fabio Puglisi, Andrea Vecchione, Barbara Belletti, Maura Sonego, Gustavo Baldassarre
{"title":"Author Correction: Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.","authors":"Alice Gambelli, Anna Nespolo, Gian Luca Rampioni Vinciguerra, Eliana Pivetta, Ilenia Pellarin, Milena S Nicoloso, Chiara Scapin, Linda Stefenatti, Ilenia Segatto, Andrea Favero, Sara D'Andrea, Maria Teresa Mucignat, Michele Bartoletti, Emilio Lucia, Monica Schiappacassi, Paola Spessotto, Vincenzo Canzonieri, Giorgio Giorda, Fabio Puglisi, Andrea Vecchione, Barbara Belletti, Maura Sonego, Gustavo Baldassarre","doi":"10.1038/s44321-024-00099-x","DOIUrl":"10.1038/s44321-024-00099-x","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1981"},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tubular insulin-induced gene 1 deficiency promotes NAD<sup>+</sup> consumption and exacerbates kidney fibrosis.","authors":"Shumin Li, Jun Qin, Yingying Zhao, Jiali Wang, Songming Huang, Xiaowen Yu","doi":"10.1038/s44321-024-00081-7","DOIUrl":"10.1038/s44321-024-00081-7","url":null,"abstract":"<p><p>Profibrotic proximal tubules (PT) were identified as a unique phenotype of proximal tubule cells (PTCs) in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, plays a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD<sup>+</sup> consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD<sup>+</sup> and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1675-1703"},"PeriodicalIF":9.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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