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 inflamed skin, which are typically dry,
scaly and itchy.
Professor Bowcock 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 continuously 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
signalling. 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-?B activation, is published in theBiochemical Journal.