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OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis
- Source :
- CELL REPORTS, Cell Reports, 30(7). Elsevier Saunders, Cell reports, 30(7), 2237-2247. CELL PRESS, Cell Reports, Vol 30, Iss 7, Pp 2237-2247.e6 (2020)
- Publication Year :
- 2020
-
Abstract
- Summary: Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues and knockin expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects mice from developing liver disease, demonstrating that apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease in hepatocyte-specific OTULIN-deficient mice. Our study reveals the critical importance of OTULIN in protecting hepatocytes from death, thereby preventing the development of chronic liver inflammation and HCC. : Hepatocellular carcinoma (HCC) develops as a result of chronic liver inflammation. Verboom et al. identify OTULIN as a critical liver-protective protein, essential in preventing hepatocyte apoptosis, which could trigger compensatory hepatocyte proliferation, chronic liver inflammation, fibrosis, and HCC.
- Subjects :
- 0301 basic medicine
Fas-Associated Death Domain Protein
NF-KAPPA-B
Apoptosis
Hepatitis
ACTIVATION
STEATOHEPATITIS
Liver disease
0302 clinical medicine
Ubiquitin
FIBROSIS
FADD
lcsh:QH301-705.5
Mice, Knockout
biology
Liver Neoplasms
TNF-ALPHA
medicine.anatomical_structure
Mathematics and Statistics
Hepatocyte
Receptor-Interacting Protein Serine-Threonine Kinases
Interferon Type I
Signal Transduction
Carcinoma, Hepatocellular
Necroptosis
CHO Cells
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
RIPK1
Cricetulus
DEFICIENT
Endopeptidases
medicine
Animals
Humans
NECROPTOSIS
Death domain
RECEPTOR
business.industry
DELETION
Biology and Life Sciences
medicine.disease
Mice, Inbred C57BL
MICE
030104 developmental biology
lcsh:Biology (General)
biology.protein
Cancer research
Steatohepatitis
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Database :
- OpenAIRE
- Journal :
- CELL REPORTS, Cell Reports, 30(7). Elsevier Saunders, Cell reports, 30(7), 2237-2247. CELL PRESS, Cell Reports, Vol 30, Iss 7, Pp 2237-2247.e6 (2020)
- Accession number :
- edsair.doi.dedup.....e06df728ec65c40085c04679b2d81cd7