EMBO Molecular MedicinePub Date : 2024-10-01Epub Date: 2024-09-06DOI: 10.1038/s44321-024-00135-w
Brigitta Stockinger, Oscar E Diaz, Emma Wincent
{"title":"The influence of AHR on immune and tissue biology.","authors":"Brigitta Stockinger, Oscar E Diaz, Emma Wincent","doi":"10.1038/s44321-024-00135-w","DOIUrl":"10.1038/s44321-024-00135-w","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2290-2298"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145402","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}
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":" ","pages":"2653"},"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}
EMBO Molecular MedicinePub 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
{"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":" ","pages":"2560-2582"},"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}
{"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":" ","pages":"2376-2401"},"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}
{"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":"11 1","pages":""},"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}
{"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":"46 1","pages":""},"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}
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
{"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":" ","pages":""},"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}
{"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":"12 1","pages":""},"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}
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