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; Ronald A. DePinho

doi:10.1038/s41467-020-18420-w

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

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38 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 language	English (US)
Article number	4766
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18420-w
State	Published - Dec 1 2020

ASJC Scopus subject areas

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

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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., ... DePinho, R. A. (2020). Telomere dysfunction activates YAP1 to drive tissue inflammation. Nature communications, 11(1), Article 4766. https://doi.org/10.1038/s41467-020-18420-w

Chakravarti, D, Hu, B, Mao, X , Rashid, A, Li, J, Li, J, Liao, WT, Whitley, EM, Dey, P, Hou, P, LaBella, KA, Chang, A, Wang, G, Spring, DJ, Deng, P, Zhao, D, Liang, X, Lan, Z, Lin, Y, Sarkar, S, Terranova, C , Deribe, YL, Blutt, SE, Okhuysen, P, Zhang, J, Vilar, E, Nielsen, OH, Dupont, A, Younes, M, Patel, KR, Shroyer, NF, Rai, K, Estes, MK, Wang, YA, Bertuch, AA & DePinho, RA 2020, 'Telomere dysfunction activates YAP1 to drive tissue inflammation', Nature communications, vol. 11, no. 1, 4766. https://doi.org/10.1038/s41467-020-18420-w

@article{07361c1326bf44d796971bc6c7bfc858,

title = "Telomere dysfunction activates YAP1 to drive tissue inflammation",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

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doi = "10.1038/s41467-020-18420-w",

language = "English (US)",

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T1 - Telomere dysfunction activates YAP1 to drive tissue inflammation

AU - Chakravarti, Deepavali

AU - Hu, Baoli

AU - Mao, Xizeng

AU - Rashid, Asif

AU - Li, Jiexi

AU - Li, Jun

AU - Liao, Wen ting

AU - Whitley, Elizabeth M.

AU - Dey, Prasenjit

AU - Hou, Pingping

AU - LaBella, Kyle A.

AU - Chang, Andrew

AU - Wang, Guocan

AU - Spring, Denise J.

AU - Deng, Pingna

AU - Zhao, Di

AU - Liang, Xin

AU - Lan, Zhengdao

AU - Lin, Yiyun

AU - Sarkar, Sharmistha

AU - Terranova, Christopher

AU - Deribe, Yonathan Lissanu

AU - Blutt, Sarah E.

AU - Okhuysen, Pablo

AU - Zhang, Jianhua

AU - Vilar, Eduardo

AU - Nielsen, Ole Haagen

AU - Dupont, Andrew

AU - Younes, Mamoun

AU - Patel, Kalyani R.

AU - Shroyer, Noah F.

AU - Rai, Kunal

AU - Estes, Mary K.

AU - Wang, Y. Alan

AU - Bertuch, Alison A.

AU - DePinho, Ronald A.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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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SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4766

ER -

Telomere dysfunction activates YAP1 to drive tissue inflammation

Abstract

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MD Anderson CCSG core facilities

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