Characterisation of the CARD14 / NF-kB Signaling Pathway
Layman's Statement: Psoriasis is a chronic inflammatory skin condition that affects around 3% of world population. Very often psoriatic patients suffer additional diseases, with psoriatic arthritis (PsA) being the most common. These diseases undermine the patient’s physical and mental health, with significant negative economic impacts. Multiple genes have been identified that are involved in the development of psoriasis, which regulate the immune system and normal skin function. Rare mutations in one of these, called CARD14, is sufficient to promote the development of psoriasis and PsA in affected individuals. These mutations activate the CARD14 protein, triggering the activation of critical inflammatory proteins called NF-κB, which then switch on expression of a number of genes in the skin involved in psoriasis. Importantly, transgenic mice lacking the CARD14 protein are fully protected in models of psoriasis, indicating an important general role for CARD14 in controlling the development of skin inflammation. Our aim is to find the key molecules required for CARD14 activation of NF-κB, as these may be good drug targets to specifically decrease the skin inflammation in psoriatic patients.
Grant Abstract: Rare mutations in caspase recruitment domain-containing protein 14 (CARD14) cause psoriasis and psoriatic arthritis. CARD14 mutation induces interaction of CARD14 with BCL10 and MALT1, triggering activation of NF-κB transcription factors and upregulated expression of psoriasis-associated pro-inflammatory genes in keratinocytes. A common variant of CARD14 (R820W) also exceeds genome-wide significance for association with psoriasis, indicating a general role for CARD14 in psoriasis pathogenesis. Consistent with this, Card14-/- mice are resistant to skin inflammation in two models of psoriasis. CARD14 therefore has a central role in regulating skin inflammation. However, the CARD14-NF-κB signaling pathway remains largely uncharacterised, and upstream activating receptors as well as the downstream signaling pathway leading to NF-κB activation have yet to be described. Using a gain-of-function CARD14 mutant, we aim to elucidate the NF-κB signaling pathway triggered by CARD14. We have developed a robust high-throughput assay for a genome-wide siRNA screen for key genes required for CARD14 activation of NF-κB. In addition, we aim to identify CARD14 activating receptors, using CARD14-deficient keratinocytes to screen for receptors that activate NF-κB in a CARD14-dependent fashion. Our goal is to identify druggable proteins in the CARD14 signaling pathway, which may provide novel opportunities for drug development in the treatment of psoriasis.