Chen, Yu-Guang;
(2022)
Investigating the role of the linear ubiquitin chain assembly complex in
lymphotoxin beta receptor signalling and obesity-derived hepatitis.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
TNF receptor superfamily (TNFR-SF)-related chronic inflammation is associated with many detrimental diseases, such as autoimmune diseases and carcinogenesis. The linear ubiquitin chain assembly complex (LUBAC) is the only E3 ligase that is capable of generating linear ubiquitin chains on targeted proteins for adequate gene activation in many TNFR-SFs. Moreover, LUBAC prevents aberrant apoptotic or necroptotic death by limiting death complex formation that is initiated by some members of the TNFR-SF with intracellular death domains such as TNFR1, TRAIL-R1, TRAIL-R2 or Fas. LTBR (lymphotoxin β receptor), a member of the TNFR-SF, is essential for the maturation of the immune system and regulation of tumour progression. However, it remains unknown, whether LUBAC plays a role in LTBR signalling and, if so, in which way it might be involved in the oncogenic and/or the tumour-suppressive arm of LTBR signalling. Addressing this open question, this thesis identified that LUBAC serves as a previously unrecognized component of the LTBR signalling complex (LTBR-SC), which regulates LTBR-associated gene activation and orchestrates the production of pro-inflammatory chemokines and cytokines. Moreover, linear ubiquitination is required for the recruitment of multiple essential proteins, including NEMO, OPTN and A20, to the LTBR-SC, which cooperatively maintains adequate LTBR-mediated signalling cascades. The second part of this thesis investigated the role of LUBAC in obesity-derived chronic hepatitis. In the liver, obesity-derived chronic hepatitis is associated with non-alcoholic fatty liver disease (NAFLD) and hepatocarcinogenesis. However, the role of LUBAC in this disease remains unclear. To this end, a murine model that mimics human obesity and non-alcoholic fatty liver disease (NAFLD) was established by administration of a choline-deficient high-fat diet (CD-HFD). Severe metabolic dysfunctions and hepatitis were observed in mice with a hepatocyte-specific HOIP deletion (HOIPH-KO) fed on CD-HFD. Moreover, this strain developed liver cancer after feeding on CD-HFD for 10 months. Intriguingly, even though hepatitis and liver cancer were ameliorated by crossing this strain with double mutant mice bearing a deletion of MLKL and partial deletion of Caspase-8, metabolic dysfunctions, such as upregulation of serum and intrahepatic triglycerides, were not reversed. Additionally, the downregulation of the important metabolic regulator kinase AMPK was detected in HOIP-deficient Hep3B cells. This deregulation of AMPK might provide a possible explanation for the phenotypic alterations characterising these mice
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the role of the linear ubiquitin chain assembly complex in lymphotoxin beta receptor signalling and obesity-derived hepatitis |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | 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 UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10145825 |
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