The role of p62/SQSTM1 and other autophagy receptors in liver homeostasis and hepatocarcinogenesis
Final Report Abstract
Persistent liver injury drives the development of chronic inflammatory liver disease (CLD), such as alcoholic and metabolism dysfunction-associated steatohepatitis (ASH and MASH) and viral hepatitis, conditions that in the long-term can progress to cirrhosis and eventually liver failure or hepatocarcinogenesis. Depending on the disease stage, preventing or inducing cell death, has started to be considered as part for the therapeutic interventions. Therefore, better understanding of the mechanisms that regulate cell death pathways is necessary. Autophagy is a survival pathway that maintains cellular homeostasis under physiological and stress conditions. Impaired autophagy has been associated with CLD pathogenesis in mouse models and ASH and MASH patients. SQSTM1/p62 is a multitasking protein that acts as autophagy receptor but also regulates various cellular pathways. Through its diverse functions, p62 has been shown to control liver injury and hepatocarcinogenesis. The main objective of this project was to dissect which specific functions of p62 and in which context promote hepatocyte death or carcinogenesis and identify other molecules with synergistic role in these processes. To this end, we have used two mouse models that develop chronic liver damage, hepatitis and liver cancer but have different genetic backgrounds in their hepatocytes (autophagy impairment vs. autophagy competence). We found that p62 accumulation can drive liver tumorigenesis through activation of KEAP1/NRF2 pathway in both models, while we could not find a correlation with mTOR activation, c-Myc upregulation or increased fibrosis. Interestingly, activation of NRF2 signaling per se was not enough to enhance carcinogenesis but required concomitant p62 aggregate formation either through acquired impairment of autophagy or its overexpression by genetic means. The importance of p62/KEAP1/NRF2 axis for hepatocarcinogenesis was also underscored in analyses of mouse and human tumor samples. The overall prevalence of this pathway in the mouse liver tumors was 10-20% and appeared higher in big-sized tumors suggesting that it becomes prominent during tumor progression. In human hepatocellular carcinomas, the prevalence of p62 overexpression reached up to 40% and showed strong correlation with the expression of KEAP1 and the NRF2 target gene NQO1. Concerning the role of p62 in liver injury, our data support its involvement in a recently described mTOR-dependent cell death inducing pathway. Importantly, this pathway appears to be specifically activated in hepatocytes under conditions of autophagy inhibition, prolonged amino acid deprivation, activation of glutaminolysis and p62 accumulation. Finally, we have performed quantitative proteomics to identify pathways redundant to p62 that could contribute to liver injury in mice with hepatic autophagy impairment. Our data confirmed the p62-dependent upregulation of NRF2- regulated genes, including ferroptosis inhibitors. In contrast, type I interferon induction and defects in selective organelle clearance persisted in the absence of p62 hinting at their additive contribution to liver injury. Indeed, genetic inhibition of type I interferon signaling in hepatocytes significantly prevented liver damage and tumorigenesis. Altogether, our results highlight contextspecific and distinct molecular mechanisms through which p62 and other parallel pathways can regulate death of non-transformed hepatocytes as well as liver cancer development. Considering that approved drugs that target mTOR, glutaminolysis and interferon signaling already exist, our results could provide a rationale for their future use in CLD and liver cancer prevention.
Publications
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p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation. Cancers, 14(10), 2436.
Kondylis, Vangelis; Schneider, Farina; Schorn, Fabian; Oikonomou, Nikos; Straub, Beate Katharina; Werner, Sabine; Rosenstiel, Philip & Pasparakis, Manolis
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SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion. Human Cell, 35(6), 1766-1784.
Yu, Xiaojie; Eischeid-Scholz, Hannah; Meder, Lydia; Kondylis, Vangelis; Büttner, Reinhard & Odenthal, Margarete
