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 Cuervo; Mark J. Czaja; M. Isabel Fiel; Yujin Hoshida; Scott L. Friedman

doi:10.1038/s41467-018-07338-z

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

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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 language	English (US)
Article number	4962
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07338-z
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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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), Article 4962. https://doi.org/10.1038/s41467-018-07338-z

Lee, YA, Noon, LA, Akat, KM, Ybanez, MD, Lee, TF, Berres, ML, Fujiwara, N, Goossens, N, Chou, HI, Parvin-Nejad, FP, Khambu, B, Kramer, EGM, Gordon, R, Pfleger, C, Germain, D, John, GR, Campbell, KN, Yue, Z, Yin, XM, Cuervo, AM, Czaja, MJ, Fiel, MI, Hoshida, Y & Friedman, SL 2018, 'Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap', Nature communications, vol. 9, no. 1, 4962. https://doi.org/10.1038/s41467-018-07338-z

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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.",

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

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AU - Lee, Ting Fang

AU - Berres, Marie Luise

AU - Fujiwara, Naoto

AU - Goossens, Nicolas

AU - Chou, Hsin I.

AU - Parvin-Nejad, Fatemeh P.

AU - Khambu, Bilon

AU - Kramer, Elisabeth G.M.

AU - Gordon, Ronald

AU - Pfleger, Cathie

AU - Germain, Doris

AU - John, Gareth R.

AU - Campbell, Kirk N.

AU - Yue, Zhenyu

AU - Yin, Xiao Ming

AU - Cuervo, Ana Maria

AU - Czaja, Mark J.

AU - Fiel, M. Isabel

AU - Hoshida, Yujin

AU - Friedman, Scott L.

PY - 2018/12/1

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N2 - 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.

AB - 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.

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

Abstract

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