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

Rune Busk Damgaard,Andrew N J Mckenzie,Hannah L Titheradge,Michael E D Allison,Susan E Davies,David Komander,Helen E Jolin

doi:10.1038/s41418-020-0532-1

Abstract

Methionine-1 (M1)-linked polyubiquitin chains conjugated by the linear ubiquitin chain assembly complex (LUBAC) control NF-κB activation, immune homoeostasis, and prevents tumour necrosis factor (TNF)-induced cell death. The deubiquitinase OTULIN negatively regulates M1-linked polyubiquitin signalling by removing the chains conjugated by LUBAC, and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. However, the cellular pathways and physiological functions controlled by OTULIN remain poorly understood. Here, we show that OTULIN prevents development of liver disease in mice and humans. In an ORAS patient, OTULIN deficiency caused spontaneous and progressive steatotic liver disease at 10–13 months of age. Similarly, liver-specific deletion of OTULIN in mice leads to neonatally onset steatosis and hepatitis, akin to the ORAS patient. OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver. In mice, steatosis progresses to steatohepatitis, fibrosis and pre-malignant tumour formation by 8 weeks of age, and by the age of 7–12 months the phenotype has advanced to malignant hepatocellular carcinoma. Surprisingly, the pathology in OTULIN-deficient livers is independent of TNFR1 signalling. Instead, we find that steatohepatitis in OTULIN-deficient livers is associated with aberrant mTOR activation, and inhibition of mTOR by rapamycin administration significantly reduces the liver pathology. Collectively, our results reveal that OTULIN is critical for maintaining liver homoeostasis and suggest that M1-linked polyubiquitin chains may play a role in regulation of mTOR signalling and metabolism in the liver.

Highlights

Prominent neonatal steatosis and aberrant mammalian target of rapamycin (mTOR) activation in OtulinΔhep mice As the phenotype in young adult OtulinΔhep mice was independent of TNFR1 signalling, we examined livers from younger OtulinΔhep mice to define the onset of the phenotype
Our findings demonstrate that mTOR activity promotes fibrosis and liver disease in OtulinΔhep mice, and that mTOR inhibition by rapamycin is insufficient to completely prevent liver pathology in these mice
We provide evidence that OTU DUB with linear linkage specificity (OTULIN) is a crucial in vivo regulator of liver homoeostasis in mice and humans, identify mTOR signalling as a surprising driver of liver disease in OTULIN-deficient mice, and show that mTOR inhibition with rapamycin can improve liver pathology caused by OTULIN deficiency

Summary

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M1-polyUb regulates pro-inflammatory nuclear factor-κB (NF-κB) signalling, gene activation, and cell death in response to engagement of tumour necrosis factor (TNF) receptor 1 (TNFR1) and a range of other immune receptors [8, 9]. Without LUBAC and M1-polyUb, TNFR1 signalling is shifted from pro-inflammatory gene activation towards induction of cell death [10, 11], which can occur via caspase-dependent apoptosis or caspase-independent necroptosis [12,13,14,15,16,17]. The primary driver of inflammation in OTULIN-deficient humans and mice is TNF signalling [31, 36], which in myeloid cells leads to LUBAC hypersignalling and NF-κB activation [31, 32]. Treatment with the mTOR inhibitor rapamycin reduces liver pathology in OTULINdeficient mice

Materials and methods

Results

Discussion

Compliance with ethical standards