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Cited by 161Autophagy in Disease and TherapyHippo pathway signaling and YAP/TAZLiver physiology and pathology

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

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Lee, Youngmin A., Noon, Luke A., Akat, Kemal M., Ybanez, Maria D., Lee, Ting-Fang, Berres, Marie-Luise, Fujiwara, Naoto, Goossens, Nicolas +16 more·2018·Nature Communications
DOI 10.1038/s41467-018-07338-zPMC PMC6251897
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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.

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  • Autophagy controls YAP/TAZ protein degradation and, as a direct consequence, proliferation in the liver.

    “Autophagy controls YAP/TAZ protein degradation and, as a direct consequence, proliferation in the liver [60].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [60]

    The Discussion (page not provided) says that impaired autophagy increases Yap protein, which drives hepatocyte proliferation, and that loss of Yap attenuates this effect. The Results (page not provided) also report increased Taz protein after Atg7 deletion, but the paper does not establish that autophagy directly degrades Taz or that Taz drives the observed proliferation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
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., Cuervo, A. M., Czaja, M. J., Fiel, M. I., Hoshida, Y., & Friedman, S. L.
Affiliations
  • Rockefeller University (US)
  • Centro de Investigacion Principe Felipe (ES)
  • Icahn School of Medicine at Mount Sinai (US)
  • Universitätsklinikum Aachen (DE)
  • The University of Texas Southwestern Medical Center (US)
  • University Hospital of Geneva (CH)
  • Indiana University Indianapolis (US)
  • Emory University (US)
Corresponding author
Lee, Youngmin A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-11-23
Volume
9
Issue
1
Pages
4962-4962
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-07338-z
PMC
PMC6251897
OpenAlex
W2901619345
Cited by
161
References
9
Citations by year
2026: 10 · 2025: 15 · 2024: 24 · 2023: 20 · 2022: 25 · 2021: 28 · 2020: 23 · 2019: 16
FWCI
13.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion, cc-by)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
  • PMC
Funders
  • U.S. Department of Defense (W81XWH-16, W81XWH, R01 DK099558, W81XWH1610363, CA150272)
  • Cancer Prevention and Research Institute of Texas (RR180016)
  • Irma T. Hirschl Trust (W81XWH-16-1-0363)
  • Icahn School of Medicine at Mount Sinai
  • Georgia Clinical and Translational Science Alliance (UL1 TR001866)
  • European Commission (ERC-2014-AdG-671231, 2007–2013, ERC-2014-AdG, ERC-2014-AdG-671231HEPCIR, FP7 2007-2013, #671231, FP7/2007, ERC-2014, 267248)
  • Deutsche Forschungsgemeinschaft (FP7/2007–2013)
  • National Institutes of Health (/ NIDDK R01, FP7/2007-2013, W81XWH, RO1DK56621, UL1TR001866)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA020709)
  • National Institute on Aging (R37AG021904, P30AG038072)
  • National Cancer Institute (P30CA196521)
  • National Institute of General Medical Sciences (R01GM122995)
  • National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK56621, DK103022, R01DK099558, T32DK007757, R01DK103022, R01DK056621, DK099558, R56DK044234, R01DK044234)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
autophagy, YAP, Hippo signaling pathway, hepatocarcinogenesis, liver regeneration, hepatocyte differentiation, ATG7, protein degradation, liver fibrosis, hepatic progenitor cells, hepatomegaly, chronic liver disease
MeSH terms
Autophagy-Related Protein 7, YAP-Signaling Proteins, Animals, Autophagy, Cell Differentiation, Female, Humans, Liver, Liver Neoplasms, Male, Phosphoproteins, Transcription Factors, Cell Cycle Proteins, Hepatocytes, Adaptor Proteins, Signal Transducing, Mice, Proteolysis, Carcinogenesis

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