Scientists in Professor Steve Ley’s laboratory at the Crick, working in close collaboration with Professor Anne Bowcock at the National Heart and Lung Institute (Imperial College London), have revealed the mechanisms behind psoriasis in patients with mutations in a gene called CARD14.
These severe mutations in CARD14 are relatively rare, but the findings may have implications for treating people with common psoriasis, which affects two to four percent of adults in the UK.
Psoriasis is a chronic inflammatory disease of the skin, characterised by patches of inflammed skin, which are typically dry, scaly and itchy.
Professor Anne Bowcock (NHLI) has previously shown that people with specific mutations in CARD14 have a high probability of developing psoriasis. These mutations cause the CARD14 protein(which is encoded by the CARD14 gene and expressed in skin cells) to activate a family of nuclear proteins that control inflammatory gene expression. These are known as gain-of-function mutations, because the resulting protein product (in this case CARD14) is altered so that it continously activates a molecular pathway that drives inflammation.
In this new study, the scientists used biochemical and cellular techniques to find out more about how CARD14 mutations lead to increased inflammation in patients with psoriasis. They investigated how variants of the CARD14 protein interact with other proteins by co-expressing them in human cells grown in the laboratory and then determining which proteins could be isolated together as a complex. The team also looked at the biological activity of the CARD14 variants in different contexts by expressing them in human skin cells and looking at the activation of downstream signalling pathways and pro-inflammatory gene expression.
Their results showed that the mutations in the CARD14 gene result in its protein product forming ‘active signalling complexes’ with proteins called BCL10 and MALT1. This activates, or turns on, MALT1 enzyme activity, which further contributes to inflammatory signaling. The scientists found that using drugs to inhibit the activity of MALT1 reduced the inflammation caused by mutant variants of CARD14.
Professor Ley said: “Our findings suggest that MALT1 inhibitors might be therapeutically beneficial for psoriasis patients with gain-of-function CARD14 mutations.
“Although these severe CARD14 mutations are relatively rare, a common genetic variant of CARD14 present in the wider population is also associated with an increased risk of developing psoriasis. This raises the interesting possibility that MALT1 inhibitors may be useful for the treatment of more common forms of psoriasis.”
The paper, Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation, is published in the Biochemical Journal.