Universität zu Köln

Verboom, Lien, Martens, Arne, Priem, Dario ORCID: 0000-0002-2527-1101, Hoste, Esther ORCID: 0000-0002-3181-431X, Sze, Mozes, Vikkula, Hanna, Van Hove, Lisette, Voet, Sofie, Roels, Jana, Maelfait, Jonathan ORCID: 0000-0002-1476-0583, Bongiovanni, Laura, de Bruin, Alain, Scott, Charlotte L., Saeys, Yvan ORCID: 0000-0002-0415-1506, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Bertrand, Mathieu J. M. and van Loo, Geert (2020). OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis. Cell Reports, 30 (7). S. 2237 - 2248. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Verboom, Lien UNSPECIFIED UNSPECIFIED UNSPECIFIED Martens, Arne UNSPECIFIED UNSPECIFIED UNSPECIFIED Priem, Dario UNSPECIFIED orcid.org/0000-0002-2527-1101 UNSPECIFIED Hoste, Esther UNSPECIFIED orcid.org/0000-0002-3181-431X UNSPECIFIED Sze, Mozes UNSPECIFIED UNSPECIFIED UNSPECIFIED Vikkula, Hanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Hove, Lisette UNSPECIFIED UNSPECIFIED UNSPECIFIED Voet, Sofie UNSPECIFIED UNSPECIFIED UNSPECIFIED Roels, Jana UNSPECIFIED UNSPECIFIED UNSPECIFIED Maelfait, Jonathan UNSPECIFIED orcid.org/0000-0002-1476-0583 UNSPECIFIED Bongiovanni, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED de Bruin, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED Scott, Charlotte L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saeys, Yvan UNSPECIFIED orcid.org/0000-0002-0415-1506 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Bertrand, Mathieu J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Loo, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-344567
DOI:	10.1016/j.celrep.2020.01.028
Journal or Publication Title:	Cell Reports
Volume:	30
Number:	7
Page Range:	S. 2237 - 2248
Date:	2020
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2211-1247
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; TNF-ALPHA; MICE; NECROPTOSIS; ACTIVATION; STEATOHEPATITIS; DEFICIENT; DELETION; RECEPTOR; FIBROSIS Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/34456