2019
DOI: 10.1101/776088
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OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Abstract: Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a deubiquitinating enzyme that specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-κB signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (T… Show more

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Cited by 5 publications
(18 citation statements)
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References 55 publications
(97 reference statements)
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“…Surprisingly, OTULIN deficiency in non-hematopoietic cells resulted in severe liver pathology in mice [25]. Hepatocyte-specific OTULIN knock-out mice develop chronic inflammatory liver disease with premalignant alterations, ultimately leading to hepatocellular carcinoma [25,68]. Loss of OTULIN expression in mouse hepatocytes increases cellular Met1 Ub levels, decreases LUBAC levels and does not induce NF-κB hyper-signaling, but sensitizes to apoptosis [25,68], in line with previous reports [7,23].…”
Section: Emerging and Novel Functions Of Otulinsupporting
confidence: 85%
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“…Surprisingly, OTULIN deficiency in non-hematopoietic cells resulted in severe liver pathology in mice [25]. Hepatocyte-specific OTULIN knock-out mice develop chronic inflammatory liver disease with premalignant alterations, ultimately leading to hepatocellular carcinoma [25,68]. Loss of OTULIN expression in mouse hepatocytes increases cellular Met1 Ub levels, decreases LUBAC levels and does not induce NF-κB hyper-signaling, but sensitizes to apoptosis [25,68], in line with previous reports [7,23].…”
Section: Emerging and Novel Functions Of Otulinsupporting
confidence: 85%
“…Hepatocyte-specific OTULIN knock-out mice develop chronic inflammatory liver disease with premalignant alterations, ultimately leading to hepatocellular carcinoma [25,68]. Loss of OTULIN expression in mouse hepatocytes increases cellular Met1 Ub levels, decreases LUBAC levels and does not induce NF-κB hyper-signaling, but sensitizes to apoptosis [25,68], in line with previous reports [7,23]. Importantly, co-deletion of TNFR1 in OTULIN-deficient mice does not ameliorate liver pathology, suggesting TNFαindependent mechanisms [25,68].…”
Section: Emerging and Novel Functions Of Otulinsupporting
confidence: 80%
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“…However, the lack of protection with RIP3 loss alone and the extensive cleaved caspase-3 labeling suggests that apoptosis is the primary driver of the pro-inflammatory phenotype in these mice. In line with these observations in systemic, inducible Otulin or Birc2/3 knock-out mice, hepatocyte specific deletion of Otulin results in hepatocyte apoptosis with resultant compensatory hyperplasia and inflammation that can progress to hepatocellular carcinoma ( Damgaard et al, 2020 ; Verboom et al, 2020 ). Increased cell death and steatosis is evident in these mice by postnatal day 9.…”
Section: Deciphering Tnf Signaling Regulation Through Genetic Mouse Mmentioning
confidence: 52%
“…Interestingly, steatosis and increased liver enzymes were also identified in an OTULIN deficient patient ( Damgaard et al, 2020 ). This hepatic injury can be alleviated by the loss of RIP1 kinase activity due to expression of the RIP1 D138N kinase dead protein, and more completely rescued by hepatocyte-specific Fadd deletion, indicating that the injury is driven by apoptosis signaling ( Verboom et al, 2020 ), although loss of TNFR1 is not sufficient to protect against liver pathology in these mice ( Damgaard et al, 2020 ). mTOR signaling is also increased in livers with hepatocyte-specific OTULIN deficiency.…”
Section: Deciphering Tnf Signaling Regulation Through Genetic Mouse Mmentioning
confidence: 99%