Back to Search
Start Over
Telomere dysfunction activates YAP1 to drive tissue inflammation
- Source :
- 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)
- Publication Year :
- 2020
-
Abstract
- 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.<br />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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 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)
- Accession number :
- edsair.doi.dedup.....540e9b4ba1f7d641278cf2e30ba3d9ce