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

Mave-, Tarm- og Leversygdomme

59 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Communications
Vol/bind	11
Udgave nummer	1
Sider (fra-til)	4766
ISSN	2041-1722
DOI	https://doi.org/10.1038/s41467-020-18420-w
Status	Udgivet - 21 sep. 2020

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10.1038/s41467-020-18420-w

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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), 4766. https://doi.org/10.1038/s41467-020-18420-w

Chakravarti, D, Hu, B, Mao, X, Rashid, A, Li, J, Li, J, Liao, W-T, 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, bind 11, nr. 1, s. 4766. https://doi.org/10.1038/s41467-020-18420-w

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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.",

keywords = "Adaptor Proteins, Signal Transducing/antagonists & inhibitors, Animals, Anti-Bacterial Agents/therapeutic use, Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors, Caspase 1/metabolism, Cell Cycle Proteins/antagonists & inhibitors, Child, Colon/metabolism, Gastrointestinal Diseases/pathology, Gastrointestinal Microbiome/drug effects, Humans, Inflammation/drug therapy, Interleukin-18/genetics, Intestinal Mucosa/metabolism, Mice, Mice, Mutant Strains, Phosphorylation, Protein Precursors/genetics, Signal Transduction, Telomerase/genetics, Telomere/pathology",

author = "Deepavali Chakravarti and Baoli Hu and Xizeng Mao and Asif Rashid and Jiexi Li and Jun Li and Wen-Ting Liao 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}",

year = "2020",

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

language = "English",

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journal = "Nature Communications",

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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 - 2020/9/21

Y1 - 2020/9/21

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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KW - Anti-Bacterial Agents/therapeutic use

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KW - Cell Cycle Proteins/antagonists & inhibitors

KW - Child

KW - Colon/metabolism

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KW - Gastrointestinal Microbiome/drug effects

KW - Humans

KW - Inflammation/drug therapy

KW - Interleukin-18/genetics

KW - Intestinal Mucosa/metabolism

KW - Mice

KW - Mice, Mutant Strains

KW - Phosphorylation

KW - Protein Precursors/genetics

KW - Signal Transduction

KW - Telomerase/genetics

KW - Telomere/pathology

U2 - 10.1038/s41467-020-18420-w

DO - 10.1038/s41467-020-18420-w

M3 - Journal article

C2 - 32958778

SN - 2041-1722

VL - 11

SP - 4766

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Telomere dysfunction activates YAP1 to drive tissue inflammation

Abstract

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