[Abstract unavailable

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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.

Background: Lysosomes are required for autophagic degradation, which can be suppressed by lysosome inhibitors. Results: Inhibition of lysosome function resulted in autophagy activation via down-regulation of MTORC1. Conclusion: Lysosomes can affect autophagy initiation in addition to its role in autophagy degradation. Significance: The finding expands lysosome function to include regulation of autophagy activation and indicates a dual effect of lysosome inhibitors in autophagy.

In our published work, we reported that HMGB1 is actively released from autophagy-deficient hepatocytes via a pathway from NRF2 to inflammasomes to promote ductular reaction, hepatic progenitor cell expansion, and tumorigenesis. We based our conclusions on multiple lines of evidence. Release of HMGB1 from autophagy-deficient hepatocytes was documented by immunoblotting, immunostaining, and ELISA analysis in different age groups of autophagy-deficient mice. The release of HMGB1 through an active mechanism is supported by kinetics analysis that shows tissue injury can be separated from the release process and by pharmacological and genetic analyses showing that the molecular elements of NRF2 and CASPASE 1 are required. The impact of HMGB1 on ductular reaction and tumor progression was also documented by both in vivo and in vitro evidence using knockout mice, cell fractionation, and transcriptional analysis. Figure 1G showed the results of an analysis of HMGB1 isoforms by mass spectrometry that was undertaken in a separate laboratory by Daniel J. Antoine. In February 2019, we learned that these data were likely compromised. We contacted the journal, and the Editorial Board gave us permission to correct the study. In the corrected version, all conclusions based on Figure 1G have been removed, and the journal has published an online version of the original article with the unreliable statements crossed out and the modified text highlighted in red (Supplemental File, Redaction). Figure 1G only suggested the formation of the released HMGB1, but carried no significance as to the releasing mechanisms and the functional significance of HMGB1 release in autophagy-deficient conditions. We thus believe that the major conclusions of the study on the releasing mechanism and functional significance of HMGB1 in autophagy-deficient conditions are independent of Figure 1G and are accurate and that the corrected paper is reliable.