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Telomere dysfunction activates YAP1 to drive tissue inflammation

Deepavali Chakravarti1, Baoli Hu1,2,3, Xizeng Mao4

  • 1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Nature Communications
|September 22, 2020
PubMed

Insights

Telomere dysfunction triggers inflammation by activating the ATM-YAP1-pro-IL-18 pathway. Inhibiting this pathway or using antibiotics reduces intestinal inflammation in mice.

Area of Science:

  • Molecular Biology
  • Immunology
  • Genetics

Background:

  • Germline telomere maintenance defects are linked to inflammatory diseases.
  • The precise mechanisms by which telomere dysfunction causes inflammation remain unclear.

Purpose of the Study:

  • To elucidate the molecular pathways linking telomere dysfunction to inflammation.
  • To investigate the role of the ATM-YAP1-pro-IL-18 axis in telomere-related inflammation.

Main Methods:

  • Investigated telomere dysfunction in human patients and mouse models.
  • Utilized molecular biology techniques to analyze protein activation and gene expression.
  • Employed pharmacological inhibitors and antibiotic treatments in mouse models.

Main Results:

  • Telomere dysfunction activates the pATM/c-ABL-YAP1 pathway, upregulating pro-IL-18.
  • The colonic microbiome activates caspase-1, maturing IL-18 and promoting IFN-γ T cell recruitment and intestinal inflammation.
  • Patients with telomere defects show DNA damage, elevated YAP1, and IL-18.
  • Therapeutic interventions (telomerase reactivation, ATM/YAP1/caspase-1 inhibition, antibiotics) reduced inflammation in mice.

Conclusions:

  • Telomere dysfunction drives intestinal inflammation via the ATM-YAP1-pro-IL-18 pathway in the epithelium.
  • This pathway represents a potential therapeutic target for inflammatory diseases associated with telomere defects.

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