Telomere dysfunction activates YAP1 to drive tissue inflammation
| Autor: | Andrew Chang, Pablo C. Okhuysen, Prasenjit Dey, Y. Alan Wang, Jianhua Zhang, Yiyun Lin, Elizabeth M. Whitley, Baoli Hu, Kyle A. LaBella, Wen Ting Liao, Asif Rashid, Kalyani R. Patel, Mary K. Estes, Kunal Rai, Zhengdao Lan, Pingping Hou, Christopher Terranova, Di Zhao, Jun Li, Guocan Wang, Sarah E. Blutt, Andrew W. Dupont, Yonathan Lissanu Deribe, Deepavali Chakravarti, Xizeng Mao, Pingna Deng, Xin Liang, Ole Haagen Nielsen, Sharmistha Sarkar, Denise J. Spring, Alison A. Bertuch, Jiexi Li, Eduardo Vilar, Ronald A. DePinho, Noah F. Shroyer, Mamoun Younes |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Telomerase Gastrointestinal Diseases General Physics and Astronomy Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Mice 0302 clinical medicine Intestinal Mucosa Phosphorylation lcsh:Science Child Cancer genetics Multidisciplinary Caspase 1 Interleukin-18 Telomere Intestinal epithelium Anti-Bacterial Agents medicine.anatomical_structure 030220 oncology & carcinogenesis medicine.symptom Signal transduction Signal Transduction Colon DNA damage Science Inflammation Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine Animals Humans Protein Precursors Transcription factor Adaptor Proteins Signal Transducing YAP-Signaling Proteins General Chemistry Mice Mutant Strains Epithelium Gastrointestinal Microbiome 030104 developmental biology Cancer research lcsh:Q |
| Zdroj: | Chakravarti, D, Hu, B, Mao, X, Rashid, A, Li, J, Li, J, Liao, W T, Whitley, E M, Dey, P, Hou, P, LaBella, K A, Chang, A, Wang, G, Spring, D J, Deng, P, Zhao, D, Liang, X, Lan, Z, Lin, Y, Sarkar, S, Terranova, C, Deribe, Y L, Blutt, S E, Okhuysen, P, Zhang, J, Vilar, E, Nielsen, O H, Dupont, A, Younes, M, Patel, K R, Shroyer, N F, Rai, K, Estes, M K, Wang, Y A, Bertuch, A A & DePinho, R A 2020, ' Telomere dysfunction activates YAP1 to drive tissue inflammation ', Nature Communications, vol. 11, 4766 . https://doi.org/10.1038/s41467-020-18420-w Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) |
| Popis: | Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation. How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation. |
| Databáze: | OpenAIRE |
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