Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap

Youngmin A. Lee, Luke A. Noon, Kemal M. Akat, Maria D. Ybanez, Ting Fang Lee, Marie Luise Berres, Naoto Fujiwara, Nicolas Goossens, Hsin I. Chou, Fatemeh P. Parvin-Nejad, Bilon Khambu, Elisabeth G.M. Kramer, Ronald Gordon, Cathie Pfleger, Doris Germain, Gareth R. John, Kirk N. Campbell, Zhenyu Yue, Xiao Ming Yin, Ana Maria CuervoMark J. Czaja, M. Isabel Fiel, Yujin Hoshida, Scott L. Friedman

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.

Original languageEnglish (US)
Article number4962
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Lee, Y. A., Noon, L. A., Akat, K. M., Ybanez, M. D., Lee, T. F., Berres, M. L., Fujiwara, N., Goossens, N., Chou, H. I., Parvin-Nejad, F. P., Khambu, B., Kramer, E. G. M., Gordon, R., Pfleger, C., Germain, D., John, G. R., Campbell, K. N., Yue, Z., Yin, X. M., ... Friedman, S. L. (2018). Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. Nature communications, 9(1), [4962]. https://doi.org/10.1038/s41467-018-07338-z