TY - JOUR
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
Y1 - 2020
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.
U2 - 10.1038/s41467-020-18420-w
DO - 10.1038/s41467-020-18420-w
M3 - Journal article
C2 - 32958778
AN - SCOPUS:85091305538
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4766
ER -