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Nat Commun. 2018 Nov 23;9(1):4962. doi: 10.1038/s41467-018-07338-z.

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

Author information

1
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ylee04@rockefeller.edu.
2
Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA. ylee04@rockefeller.edu.
3
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
4
CIBERDEM, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.
5
Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA.
6
Department of Internal Medicine III, University Hospital RWTH Aachen, 52074, Aachen, Germany.
7
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
8
Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, Tx 75390, USA.
9
Division of Gastroenterology and Hepatology, Geneva University Hospital, 1205, Geneva, Switzerland.
10
Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
11
Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12
Department for Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
13
Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
14
Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, 10029, New York, USA.
15
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
16
Department of Medicine, Emory University School of Medicine, Atlanta, GA, GA 30307, USA.

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.

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