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Molecular and functional characterisation of linear ubiquitination in the liver

Shimizu, Y; (2017) Molecular and functional characterisation of linear ubiquitination in the liver. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Linear ubiquitination is one of the key post-translational modifications that regulate immune signalling pathways and cell death. The only known enzyme complex capable of forming linear ubiquitin chains de novo is the linear ubiquitin chain assembly complex (LUBAC), and its catalytic core component is HOIP. To understand the underlying mechanisms of liver inflammation and associated carcinogenesis, the physiological role of LUBAC in the liver parenchyma was investigated. Here I report that HOIP deficiency in liver parenchymal cells triggered spontaneous cell death and inflammation in murine livers at early stages and tumourigenesis later in life. HOIP-deficient livers displayed increased cell death, including apoptosis, regeneration and immune cell infiltration. TNF-induced NF-κB activation was attenuated in HOIP-deficient primary hepatocytes and they were more susceptible to TNF-induced cell death independently of their impaired gene- activatory capacity. Unexpectedly, however, liver damage observed in HOIPdeficient livers was TNFR1-independent as co-deletion of TNFR1 did not ameliorate cell death in HOIP-deficient livers whilst mitigating their inflammation. In accordance with increased cell death, HOIP-deficient hepatocytes displayed enhanced formation of a death-inducing signalling complex containing FADD, RIPK1, caspase-8 and c-FLIP. This elevated signalling complex formation in HOIP-deficient hepatocytes was independent of lowered gene-activatory capacity and the presence of TNFR1. Moreover, combined ablation of systemic caspase-8 and MLKL completely prevented liver damage due to loss of HOIP, whereas MLKL deficiency did not have a beneficial effect. This demonstrates a crucial role for aberrant cell death in HOIPdeficient livers. Collectively, these results identify LUBAC as a previously unrecognised tumour suppressor, which acts by restraining TNFR1-independent FADD-RIPK1-caspase-8 complex formation and caspase-8-dependent apoptosis, regardless of its gene-regulatory function, in hepatocytes to prevent liver damage and inflammation.

Type: Thesis (Doctoral)
Title: Molecular and functional characterisation of linear ubiquitination in the liver
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/1543041
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