Pub Date : 2024-10-01DOI: 10.1038/s44321-024-00125-y
Mihyun Bae, Junyeop Daniel Roh, Youjoung Kim, Seong Soon Kim, Hye Min Han, Esther Yang, Hyojin Kang, Suho Lee, Jin Yong Kim, Ryeonghwa Kang, Hwajin Jung, Taesun Yoo, Hyosang Kim, Doyoun Kim, Heejeong Oh, Sungwook Han, Dayeon Kim, Jinju Han, Yong Chul Bae, Hyun Kim, Sunjoo Ahn, Andrew M Chan, Daeyoup Lee, Jin Woo Kim, Eunjoon Kim
{"title":"Author Correction: SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function.","authors":"Mihyun Bae, Junyeop Daniel Roh, Youjoung Kim, Seong Soon Kim, Hye Min Han, Esther Yang, Hyojin Kang, Suho Lee, Jin Yong Kim, Ryeonghwa Kang, Hwajin Jung, Taesun Yoo, Hyosang Kim, Doyoun Kim, Heejeong Oh, Sungwook Han, Dayeon Kim, Jinju Han, Yong Chul Bae, Hyun Kim, Sunjoo Ahn, Andrew M Chan, Daeyoup Lee, Jin Woo Kim, Eunjoon Kim","doi":"10.1038/s44321-024-00125-y","DOIUrl":"10.1038/s44321-024-00125-y","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145400","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}
Pub Date : 2024-10-01Epub Date: 2024-08-28DOI: 10.1038/s44321-024-00118-x
Hemanth Tummala, Amanda J Walne, Mohsin Badat, Manthan Patel, Abigail M Walne, Jenna Alnajar, Chi Ching Chow, Ibtehal Albursan, Jennifer M Frost, David Ballard, Sally Killick, Peter Szitányi, Anne M Kelly, Manoj Raghavan, Corrina Powell, Reinier Raymakers, Tony Todd, Elpis Mantadakis, Sophia Polychronopoulou, Nikolas Pontikos, Tianyi Liao, Pradeep Madapura, Upal Hossain, Tom Vulliamy, Inderjeet Dokal
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.
先天性角化不良症(DC)是一种罕见的遗传性骨髓衰竭综合征,由主要影响端粒生物学的基因突变引起。大约 35% 的病例在基因水平上仍未定性。为了探索遗传特征,我们对大量临床诊断的DC病例以及表现出类似DC特征的病例(被称为 "类DC"(DCL))进行了遗传研究。这使我们在已知基因位点和新型 X 连锁基因 POLA1 中发现了几个新的致病变体。此外,我们还在不同家族的多个病例中发现了 POT1 和 ZCCHC8 的几个新型变体,从而扩大了 DC 和 DCL 表型的等位基因系列。对新型 POLA1 和 POT1 变体的功能特性分析表明,这些变体对与引物酶、CTC1-STN1-TEN1(CST)和庇护素亚基复合物的蛋白-蛋白相互作用有致病作用,而蛋白-蛋白相互作用对端粒的维持至关重要。ZCCHC8变体显示了ZCCHC8缺乏和普遍转录的迹象,引发了患者血液中的炎症。总之,我们的研究扩展了当前的遗传结构,并拓宽了我们对DC和DCL疾病机制的理解。
{"title":"The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.","authors":"Hemanth Tummala, Amanda J Walne, Mohsin Badat, Manthan Patel, Abigail M Walne, Jenna Alnajar, Chi Ching Chow, Ibtehal Albursan, Jennifer M Frost, David Ballard, Sally Killick, Peter Szitányi, Anne M Kelly, Manoj Raghavan, Corrina Powell, Reinier Raymakers, Tony Todd, Elpis Mantadakis, Sophia Polychronopoulou, Nikolas Pontikos, Tianyi Liao, Pradeep Madapura, Upal Hossain, Tom Vulliamy, Inderjeet Dokal","doi":"10.1038/s44321-024-00118-x","DOIUrl":"10.1038/s44321-024-00118-x","url":null,"abstract":"<p><p>Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092505","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}
There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified CXCR3-antagonist from our compound library, namely 7D, which inhibited all serotypes of DENV in vitro. With a half-life of ~2.85 h in plasma and no significant toxicity, 7D supplementation (8 mg/kg-body-weight) to DENV2-infected IFNα/β/γR-/-AG129 or wild-type C57BL6 mice increased synthesis of IFN-α/β and IFN-λ, and rescued disease symptoms like thrombocytopenia, leukopenia and vascular-leakage, with improved survival. 7D, having the property to inhibit Sirt-1 deacetylase, promoted acetylation and phosphorylation of STAT3, which in-turn increased plasmablast proliferation, germinal-center maturation and synthesis of neutralizing-antibodies against DENV2 in mice. A STAT3-inhibitor successfully inhibited these effects of 7D. Together, these observations identify compound 7D as a stimulator of IFN-α/β/λ synthesis via CXCL4:CXCR3:p38:IRF3 signaling, and a booster for neutralizing-antibody generation by promoting STAT3-acetylation in plasmablasts, capable of protecting dengue infection.
{"title":"7D, a small molecule inhibits dengue infection by increasing interferons and neutralizing-antibodies via CXCL4:CXCR3:p38:IRF3 and Sirt1:STAT3 axes respectively.","authors":"Kishan Kumar Gaur, Tejeswara Rao Asuru, Mitul Srivastava, Nitu Singh, Nikil Purushotham, Boja Poojary, Bhabatosh Das, Sankar Bhattacharyya, Shailendra Asthana, Prasenjit Guchhait","doi":"10.1038/s44321-024-00137-8","DOIUrl":"10.1038/s44321-024-00137-8","url":null,"abstract":"<p><p>There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified CXCR3-antagonist from our compound library, namely 7D, which inhibited all serotypes of DENV in vitro. With a half-life of ~2.85 h in plasma and no significant toxicity, 7D supplementation (8 mg/kg-body-weight) to DENV2-infected IFNα/β/γR<sup>-/-</sup>AG129 or wild-type C57BL6 mice increased synthesis of IFN-α/β and IFN-λ, and rescued disease symptoms like thrombocytopenia, leukopenia and vascular-leakage, with improved survival. 7D, having the property to inhibit Sirt-1 deacetylase, promoted acetylation and phosphorylation of STAT3, which in-turn increased plasmablast proliferation, germinal-center maturation and synthesis of neutralizing-antibodies against DENV2 in mice. A STAT3-inhibitor successfully inhibited these effects of 7D. Together, these observations identify compound 7D as a stimulator of IFN-α/β/λ synthesis via CXCL4:CXCR3:p38:IRF3 signaling, and a booster for neutralizing-antibody generation by promoting STAT3-acetylation in plasmablasts, capable of protecting dengue infection.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282187","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}
There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.
{"title":"Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males.","authors":"Małgorzata Rydzanicz,Bozena Kuzniewska,Marta Magnowska,Tomasz Wójtowicz,Aleksandra Stawikowska,Anna Hojka,Ewa Borsuk,Ksenia Meyza,Olga Gewartowska,Jakub Gruchota,Jacek Miłek,Patrycja Wardaszka,Izabela Chojnicka,Ludwika Kondrakiewicz,Dorota Dymkowska,Alicja Puścian,Ewelina Knapska,Andrzej Dziembowski,Rafał Płoski,Magdalena Dziembowska","doi":"10.1038/s44321-024-00147-6","DOIUrl":"https://doi.org/10.1038/s44321-024-00147-6","url":null,"abstract":"There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.
视黄酸诱导基因 I(RIG-I)是一种参与先天性免疫的模式识别受体,但它在适应性免疫,特别是在 CD8+ T 细胞抗肿瘤免疫中的作用仍不清楚。在这里,我们证明了 RIG-I 在肿瘤浸润的 CD8+ T 细胞中上调,它作为细胞内检查点负调控 CD8+ T 细胞功能并限制抗肿瘤免疫。从机理上讲,RIG-I 在 CD8+ T 细胞中的上调是由活化的 T 细胞诱导的,并直接抑制 AKT/糖酵解信号通路。此外,敲除 RIG-I 可增强被收养转移 T 细胞对实体瘤的疗效,抑制 RIG-I 可增强对 PD-1 阻断的反应。总之,我们的研究发现 RIG-I 是一种细胞内检查点,也是在癌症免疫疗法中缓解 T 细胞抑制性限制的潜在靶点,可以单独使用,也可以与免疫检查点抑制剂联合使用。
{"title":"RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity.","authors":"Xiaobing Duan,Jiali Hu,Yuncong Zhang,Xiaoguang Zhao,Mingqi Yang,Taoping Sun,Siya Liu,Xin Chen,Juan Feng,Wenting Li,Ze Yang,Yitian Zhang,Xiaowen Lin,Dingjie Liu,Ya Meng,Guang Yang,Qiuping Lin,Guihai Zhang,Haihong Lei,Zhengsheng Yi,Yanyan Liu,Xiaobing Liang,Yujuan Wu,Wenqing Diao,Zesong Li,Haihai Liang,Meixiao Zhan,Hong-Wei Sun,Xian-Yang Li,Ligong Lu","doi":"10.1038/s44321-024-00136-9","DOIUrl":"https://doi.org/10.1038/s44321-024-00136-9","url":null,"abstract":"Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1038/s44321-024-00139-6
Hung-Chang Chen,Nico Mueller,Katherine Stott,Chrysa Kapeni,Eilidh Rivers,Carolin M Sauer,Flavio Beke,Stephen J Walsh,Nicola Ashman,Louise O'Brien,Amir Rafati Fard,Arman Ghodsinia,Changtai Li,Fadwa Joud,Olivier Giger,Inti Zlobec,Ioana Olan,Sarah J Aitken,Matthew Hoare,Richard Mair,Eva Serrao,James D Brenton,Alicia Garcia-Gimenez,Simon E Richardson,Brian Huntly,David R Spring,Mikkel-Ole Skjoedt,Karsten Skjødt,Marc de la Roche,Maike de la Roche
{"title":"Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types.","authors":"Hung-Chang Chen,Nico Mueller,Katherine Stott,Chrysa Kapeni,Eilidh Rivers,Carolin M Sauer,Flavio Beke,Stephen J Walsh,Nicola Ashman,Louise O'Brien,Amir Rafati Fard,Arman Ghodsinia,Changtai Li,Fadwa Joud,Olivier Giger,Inti Zlobec,Ioana Olan,Sarah J Aitken,Matthew Hoare,Richard Mair,Eva Serrao,James D Brenton,Alicia Garcia-Gimenez,Simon E Richardson,Brian Huntly,David R Spring,Mikkel-Ole Skjoedt,Karsten Skjødt,Marc de la Roche,Maike de la Roche","doi":"10.1038/s44321-024-00139-6","DOIUrl":"https://doi.org/10.1038/s44321-024-00139-6","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1038/s44321-024-00144-9
Angelisa Frasca, Federica Miramondi, Erica Butti, Marzia Indrigo, Maria Balbontin Arenas, Francesca M Postogna, Arianna Piffer, Francesco Bedogni, Lara Pizzamiglio, Clara Cambria, Ugo Borello, Flavia Antonucci, Gianvito Martino, Nicoletta Landsberger
The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analyzed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT.
{"title":"Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway.","authors":"Angelisa Frasca, Federica Miramondi, Erica Butti, Marzia Indrigo, Maria Balbontin Arenas, Francesca M Postogna, Arianna Piffer, Francesco Bedogni, Lara Pizzamiglio, Clara Cambria, Ugo Borello, Flavia Antonucci, Gianvito Martino, Nicoletta Landsberger","doi":"10.1038/s44321-024-00144-9","DOIUrl":"10.1038/s44321-024-00144-9","url":null,"abstract":"<p><p>The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analyzed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.
肠纤维化是克罗恩病(CD)患者致残的主要原因,但目前尚缺乏有效的治疗策略。在此,我们报告了对278名克罗恩病患者和28名健康对照者的肠道微生物群和粪便/血液代谢物进行的多组学分析,发现了中重度肠纤维化患者肠道微生物群(如Lachnospiraceae、Ruminococcaceae、Muribaculaceae、Saccharimonadales)和代谢物(如L-天冬氨酸、谷氨酰胺、乙基甲基乙酸)的特征性改变。通过整合多组学数据与磁共振肠造影特征,建立了微生物代谢物与肠纤维化相关形态学改变之间的潜在联系。这些潜在联系由氨基酸(如 L-天门冬氨酸)、初级胆汁酸和谷氨酰胺的特定组合介导。最后,我们提供了 L-天门冬氨酸在体外和体内加重肠纤维化的因果证据。总之,我们为肠道微生物群及其代谢产物促进 CD 肠道纤维化的假说提供了生物学上合理的解释,同时也为治疗试验确定了潜在的靶点。
{"title":"Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease.","authors":"Xuehua Li,Shixian Hu,Xiaodi Shen,Ruonan Zhang,Caiguang Liu,Lin Xiao,Jinjiang Lin,Li Huang,Weitao He,Xinyue Wang,Lili Huang,Qingzhu Zheng,Luyao Wu,Canhui Sun,Zhenpeng Peng,Minhu Chen,Ziping Li,Rui Feng,Yijun Zhu,Yangdi Wang,Zhoulei Li,Ren Mao,Shi-Ting Feng","doi":"10.1038/s44321-024-00129-8","DOIUrl":"https://doi.org/10.1038/s44321-024-00129-8","url":null,"abstract":"Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.
{"title":"ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer.","authors":"Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou","doi":"10.1038/s44321-024-00138-7","DOIUrl":"https://doi.org/10.1038/s44321-024-00138-7","url":null,"abstract":"Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}