A team of researchers from the Vlaams Institute for Biotechnology (VIB) in Belgium discovered a molecular mechanism by which specific mutations in the protein coding gene CARD14 can lead to abnormal inflammation in people suffering from psoriasis. The researchers published their observations, titled “The paracaspase MALT1 mediates CARD14‐induced signaling in keratinocytes,” in the journal EMBO Reports.
Psoriasis is a chronic autoimmune disorder that affects about 3 percent of people in the developed world. Psoriasis is considered a genetic disorder largely dependent on several environmental factors. It is generally characterized by abnormal and inflamed skin. There is currently no treatment for the cause of the disease, and the latest therapeutic approaches treat only the symptoms.
The underlying causes of psoriasis include the activation of the immune system, leading to high inflammation and proliferation in the skin. A well known genetic factor that can cause the development of psoriasis is related to CARD14 gene mutations. These mutations can enable the CARD14 protein to activate another regulatory protein, called NF-kB, that controls inflammation and psoriasis.
Inna Afonina and Elien Van Nuffel, under the leadership of Prof. Rudi Beyaert, demonstrated the key role for a protease, called paracaspase MALT1 in CARD14-induced signaling. They confirmed that CARD14 activates two MALT1-dependent signaling mechanisms (NF-kB and p38/JNK signaling), and induces MALT1 proteolytic activity.
The physiological relevance for psoriasis was illustrated by their observation that the enhanced ability of psoriasis-associated CARD14 mutants to activate NF-kB relative to wild-type CARD14 is more pronounced when MALT1 is expressed. CARD14 mutants were demonstrated to more efficiently activate MALT1 proteolytic activity.
Moreover, mutant CARD14-induced immune response and inflammation in human keratinocytes can be strongly decreased by MALT1 deficiency or a MALT1 protease inhibitor that can offer a new therapeutic target in psoriasis associated with CARD14 mutation.
Psoriasis topical treatment with MALT1 inhibitors were also found to induce less adverse effects than systemic inhibition of MALT1 activity. Although it is more challenging to develop molecules specifically targeting the interaction of mutant CARD14 with MALT1, it can allow them to specifically interfere with pathological MALT1 activation in keratinocytes and offer the safest approach to treat psoriasis patients with CARD14 mutations
“Our findings raise the interesting possibility that MALT1 inhibitors might be therapeutically beneficial for psoriasis patients with CARD14 mutations. Whether MALT1 inhibitors may also be useful for the treatment of more common forms of psoriasis is currently under investigation,” said VIB Prof. Rudi Beyaert.
“We found that pharmacological treatment of human skin cells with drugs that inhibit the activity of MALT1 reduced the production of inflammation-promoting proteins caused by mutant variants of CARD14,” added Prof. Rudi Beyaert. “We hope to find an industrial partner to take these promising results a step further in the search for a psoriasis cure.”
