Characterisation of the CARD14/ NF-ĸB pathway

• Main Author: O'Sullivan, Paul Anthony
• Format: Dissertation
• Language: English
• Published: Imperial College London 2020
• DOI: 10.25560/97571

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.