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:
CreatorsEmailORCIDORCID Put Code
Verboom, LienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martens, ArneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Priem, DarioUNSPECIFIEDorcid.org/0000-0002-2527-1101UNSPECIFIED
Hoste, EstherUNSPECIFIEDorcid.org/0000-0002-3181-431XUNSPECIFIED
Sze, MozesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vikkula, HannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Hove, LisetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voet, SofieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roels, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maelfait, JonathanUNSPECIFIEDorcid.org/0000-0002-1476-0583UNSPECIFIED
Bongiovanni, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Bruin, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, Charlotte L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saeys, YvanUNSPECIFIEDorcid.org/0000-0002-0415-1506UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Bertrand, Mathieu J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Loo, GeertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
NF-KAPPA-B; TNF-ALPHA; MICE; NECROPTOSIS; ACTIVATION; STEATOHEPATITIS; DEFICIENT; DELETION; RECEPTOR; FIBROSISMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/34456

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