Bcl10 Lab Reagents

TAK1 lessens the activity of the paracaspase MALT1 during T cell receptor signaling

The CARMA1-BCL10-MALT1 (CBM) complex couples antigen receptors to the activation of Nuclear Factor κB (NF-κB) transcription factors in T/B lymphocytes.

Within this signalosome, the MALT1 paracaspase serves dual roles: it is a crucial adaptor for signal transduction to NF-κB signaling, and a protease that shapes NF-κB activity and lymphocyte activation. Although a subtle choreography of ubiquitination and phosphorylation orchestrate the CBM, how precisely this complex and MALT1 enzyme are regulated continue to be elucidated.

Here, we report that the chemical inhibition or the siRNA-based silencing of transforming growth factor beta-activated kinase 1 (TAK1), a known partner of the CBM complex required for NF-κB activation, enhanced the processing of MALT1 substrates.

Bcl10 Laboratory PhD

We further show that the assembly of the CBM as well as the ubiquitination of MALT1 was augmented when TAK1 was inhibited. Thus, TAK1 may initiate a negative feedback loop to finely tune the CBM complex activity.

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MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice

CARD14 gain-of-function mutations cause psoriasis in humans and mice. Together with BCL10 and the protease MALT1, mutant CARD14 forms a signaling node that mediates increased NF-κB signaling and proinflammatory gene expression in keratinocytes.

However, it remains unclear whether psoriasis in response to CARD14 hyperactivation is keratinocyte-intrinsic or requires CARD14 signaling in other cells. Moreover, the in vivo effect of MALT1 targeting on mutant CARD14-induced psoriasis has not yet been documented.

Here, we show that inducible keratinocyte-specific expression of CARD14E138A in mice rapidly induces epidermal thickening and inflammation as well as increased expression of several genes associated with psoriasis in humans.

Keratinocyte-specific MALT1 deletion as well as oral treatment of mice with a specific MALT1 protease inhibitor strongly reduces psoriatic skin disease in CARD14E138A mice.

Together, these data illustrate a keratinocyte-intrinsic causal role of enhanced CARD14/MALT1 signaling in the pathogenesis of psoriasis and show the potential of MALT1 inhibition for the treatment of psoriasis.