Characterisation of the CARD14/ NF-ĸB Pathway
File(s)
Author(s)
O'Sullivan, Paul Anthony
Type
Thesis
Abstract
Familial inherited and de novo mutations in CARD14 cause a number of autoinflammatory skin disorders in humans. Genome wide association studies have also linked CARD14 to the development of common psoriasis. CARD14 is a member of a family of adaptor proteins that activate NF-ĸB transcription factors. At the initiation of this study, it was known that gain-of-function mutation of CARD14 promote its ability to activate NF-ĸB. However, the underlying molecular mechanisms involved had not been investigated. Thus, this study set out to characterise the CARD14/ NF-ĸB signalling pathway with a range of methodologies. Biochemical results described herein demonstrate that gain-of-function mutant CARD14 protein signals via a complex and highly regulated signalosome to activate the canonical NF-ĸB pathway. It is also shown that CARD14 signals for a broad transcriptomic response in keratinocytes, helping to understand the disruption of skin homeostasis in psoriatic patients. Lastly, the CARD14 signalosome appears to assemble at and signal from the microtubule-vesicular network.
Version
Open Access
Date Issued
2019-11
Date Awarded
2020-06
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Ley, Steven
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)