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Telomere dysfunction activates YAP1 to drive tissue inflammation

Chakravarti, Deepavali, Hu, Baoli, Mao, Xizeng, Rashid, Asif, Li, Jiexi, Li, Jun, Liao, Wen-ting, Whitley, Elizabeth M., Dey, Prasenjit, Hou, Pingping, LaBella, Kyle A., Chang, Andrew, Wang, Guocan, Spring, Denise J., Deng, Pingna, Zhao, Di, Liang, Xin, Lan, Zhengdao, Lin, Yiyun, Sarkar, Sharmistha, Terranova, Christopher, Deribe, Yonathan Lissanu, Blutt, Sarah E., Okhuysen, Pablo, Zhang, Jianhua, Vilar, Eduardo, Nielsen, Ole Haagen, Dupont, Andrew, Younes, Mamoun, Patel, Kalyani R., Shroyer, Noah F., Rai, Kunal, Estes, Mary K., Wang, Y. Alan, Bertuch, Alison A., DePinho, Ronald A.·2020·Nature Communications
DOI 10.1038/s41467-020-18420-wPMC PMC7505960
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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.

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Metadata

Authors
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.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-09-21
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-18420-w
PMC
PMC7505960
Cited by
77
References
5
Language
en
Licence
Funders
U.S. Department of Health & Human Services | National Institutes of Health (K99 CA218891, R01 CA084628)

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