OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

Damgaard, R. B.; Jolin, H. E.; Allison, M. E.; Davies, S. E.; McKenzie, A. N.; Komander, D.

doi:10.1101/776021

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bioRxiv · 10.1101/776021

OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

Damgaard, R. B.·Jolin, H. E.·Allison, M. E.·Davies, S. E.·McKenzie, A. N.·Komander, D.

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Abstract

The deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin chains to regulate TNF-mediated inflammation and cell death, but the physiological role of OTULIN outside the immune system is poorly understood. Here, we identify OTULIN as a liver tumour suppressor in mice. Hepatocyte-specific OTULIN deletion causes spontaneous steatohepatitis, extensive fibrosis, and pre-malignant tumours by eight weeks of age, which progresses to hepatocellular carcinoma by 7-12 months. OTULIN deficiency triggers apoptosis and inflammation in the liver, but surprisingly, steatohepatitis and pre-malignant growth is independent of TNFR1 signalling. Instead, the pathology in OTULIN-deficient livers is associated with increased mTOR activation, and mTOR inhibition with rapamycin reduces fibrosis and pre-malignant growth. This demonstrates that OTULIN is critical for maintaining liver homeostasis and preventing mTOR-driven liver disease.

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Damgaard, R. B., Jolin, H. E., Allison, M. E., Davies, S. E., McKenzie, A. N., Komander, D.. 2019-09-19. OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer. https://doi.org/10.1101/776021

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