The paracaspase MALT1 mediates CARD14‐induced signaling in keratinocytes

Abstract

Mutations in CARD14 have recently been linked to psoriasis susceptibility. CARD14 is an epidermal regulator of NF-jB activation. However, the ability of CARD14 to activate other signaling pathways as well as the biochemical mechanisms that mediate and regulate its function remain to be determined. Here, we report that in addition to NF-jB signaling, CARD14 activates p38 and JNK MAP kinase pathways, all of which are dependent on the paracaspase MALT1. Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis-associated CARD14 mutations. Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes. Collectively, our findings demonstrate a novel role for MALT1 in CARD14-induced signaling and indicate MALT1 as a valuable therapeutic target in psoriasis.

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

“…CARD14 GoF mutation causes spontaneous signalosome formation in primary human keratinocytes, which is dependent on a functional CARD domain Consistent with previous reports, CARD14 E138A and DE138 mutants both caused enhanced NF-kB and AP-1 activation in vitro in HEK293 cells compared with wild-type (WT) CARD14, with the E138A mutant showing a more potent response (see Supplementary Figure S1a online) (Afonina et al, 2016;Li et al, 2015). CARD14 E138A and CARD14 DE138 GoF mutants were also overexpressed in primary keratinocytes and HEK293 cells and were observed to interact with endogenous Bcl10 by co-immunoprecipitation ( Figure 1a, and see Supplementary Figure S1b), whereas Bcl10 interaction with CARD14 WT was below detectable levels.…”

“…CARD14 E138A and CARD14 DE138 GoF mutants were also overexpressed in primary keratinocytes and HEK293 cells and were observed to interact with endogenous Bcl10 by co-immunoprecipitation ( Figure 1a, and see Supplementary Figure S1b), whereas Bcl10 interaction with CARD14 WT was below detectable levels. Because this was contrary to previous findings (Afonina, 2016;Scudiero, 2011), we sought to assess other means of CARD14 activity. There was a reduction of Bcl10 expression observed in the presence of all three CARD14 constructs in HEK293 cells (see Supplementary Figure S1b) and a decrease of CARD14 mutant expression in primary keratinocytes (Figure 1a).…”

CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis

“…In addition to the full-length form (CARD14fl), a shorter splice variant (CARD14sh), which lacks a part of the membraneassociated guanylate kinase domain, has been described (Scudiero et al, 2011). The functional differences between CARD14fl and CARD14sh have remained elusive thus far, as they seem equally potent in mounting an NF-kB response (Afonina et al, 2016). A third splice variant, CARD14cardless, lacks the CARD domain as well as part of the CC domain and the SH3 and GUK domains.…”

Applied cultural and social studies are needed for a sustainable reduction of genetic disease incidence

“…The truth is sadly far more mundane and slow, with an average time frame of years to decades from initial basic discovery (which also is a slow and tedious process) until a treatment reaches the clinic (Morris et al, 2011). I have personally experienced this in basic biomedical research, far away from a usable treatment, that reports of a new mechanism to target in general for autoimmune diseases (Coornaert et al, 2008) or specifically for multiple sclerosis (Mc Guire et al, 2014) or psoriasis (Afonina et al, 2016) led to a media spin which gave many sufferers of these diseases false hopes. These high expectations on what science can deliver on a short term basis is an ethical problem in science communication (Bubela et al, 2012).…”