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Telomere dysfunction activates YAP1 to drive tissue inflammation

Author

Listed:
  • Deepavali Chakravarti

    (The University of Texas MD Anderson Cancer Center)

  • Baoli Hu

    (The University of Texas MD Anderson Cancer Center
    Children’s Hospital of Pittsburgh of UPMC
    University of Pittsburgh School of Medicine)

  • 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
    School of Basic Medical Sciences, Southern Medical University)

  • Elizabeth M. Whitley

    (The University of Texas MD Anderson Cancer Center)

  • Prasenjit Dey

    (The University of Texas MD Anderson Cancer Center
    Roswell Park Comprehensive 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
    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
    Emory University)

  • 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
    Baylor College of Medicine)

  • Ronald A. DePinho

    (The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • 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 & D, 2020. "Telomere dysfunction activates YAP1 to drive tissue inflammation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18420-w
    DOI: 10.1038/s41467-020-18420-w
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