Telomere dysfunction activates YAP1 to drive tissue inflammation

Deepavali Chakravarti, Baoli Hu, Xizeng Mao, Asif Rashid, Jiexi Li, Jun Li, Wen ting Liao, Elizabeth M. Whitley, Prasenjit Dey, Pingping Hou, Kyle A. LaBella, Andrew Chang, Guocan Wang, Denise J. Spring, Pingna Deng, Di Zhao, Xin Liang, Zhengdao Lan, Yiyun Lin, Sharmistha SarkarChristopher Terranova, Yonathan Lissanu Deribe, Sarah E. Blutt, Pablo Okhuysen, Jianhua Zhang, Eduardo Vilar, Ole Haagen Nielsen, Andrew Dupont, Mamoun Younes, Kalyani R. Patel, Noah F. Shroyer, Kunal Rai, Mary K. Estes, Y. Alan Wang, Alison A. Bertuch, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Article number4766
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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