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 Sarkar, Christopher 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 and Ronald A. DePinho ()
Additional contact information
Deepavali Chakravarti: The University of Texas MD Anderson Cancer Center
Baoli Hu: The University of Texas MD Anderson Cancer Center
Xizeng Mao: The University of Texas MD Anderson Cancer Center
Asif Rashid: The University of Texas MD Anderson Cancer Center
Jiexi Li: The University of Texas MD Anderson Cancer Center
Jun Li: The University of Texas MD Anderson Cancer Center
Wen-ting Liao: The University of Texas MD Anderson Cancer Center
Elizabeth M. Whitley: The University of Texas MD Anderson Cancer Center
Prasenjit Dey: The University of Texas MD Anderson Cancer Center
Pingping Hou: The University of Texas MD Anderson Cancer Center
Kyle A. LaBella: The University of Texas MD Anderson Cancer Center
Andrew Chang: The University of Texas MD Anderson Cancer Center
Guocan Wang: The University of Texas MD Anderson Cancer Center
Denise J. Spring: The University of Texas MD Anderson Cancer Center
Pingna Deng: The University of Texas MD Anderson Cancer Center
Di Zhao: The University of Texas MD Anderson Cancer Center
Xin Liang: The University of Texas MD Anderson Cancer Center
Zhengdao Lan: The University of Texas MD Anderson Cancer Center
Yiyun Lin: The University of Texas MD Anderson Cancer Center
Sharmistha Sarkar: The University of Texas MD Anderson Cancer Center
Christopher Terranova: The University of Texas MD Anderson Cancer Center
Yonathan Lissanu Deribe: The University of Texas MD Anderson Cancer Center
Sarah E. Blutt: Baylor College of Medicine
Pablo Okhuysen: The University of Texas MD Anderson Cancer Center
Jianhua Zhang: The University of Texas MD Anderson Cancer Center
Eduardo Vilar: The University of Texas MD Anderson Cancer Center
Ole Haagen Nielsen: University of Copenhagen
Andrew Dupont: The University of Texas Health Science Center at Houston
Mamoun Younes: University of Texas Health Science Center at Houston, McGovern Medical School and Memorial Hermann Hospital-TMC
Kalyani R. Patel: Texas Children’s Hospital
Noah F. Shroyer: Section of Gastroenterology and Hepatology, Baylor College of Medicine
Kunal Rai: The University of Texas MD Anderson Cancer Center
Mary K. Estes: Baylor College of Medicine
Y. Alan Wang: The University of Texas MD Anderson Cancer Center
Alison A. Bertuch: Baylor College of Medicine
Ronald A. DePinho: The University of Texas MD Anderson Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18420-w

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