MALT1 Auto-Proteolysis Is Essential for NF-κB-Dependent Gene Transcription in Activated Lymphocytes

Abstract

Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor–mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

“…Our data suggest that HOIL1 impedes NF-κB independently of IKK, although the exact mechanism remains unclear. In addition to inactivating the NF-κB negative regulators A20 and RelB (Coornaert et al, 2008;Hailfinger et al, 2011), MALT1 initiates an IKK-independent NF-κB pathway through its own autoproteolysis (Baens et al, 2014) and participates in c-Rel activation (Ferch et al, 2009(Ferch et al, , 2007. Nevertheless, our data suggests that HOIL1 belongs, together with A20 and RelB (Coornaert et al, 2008;Hailfinger et al, 2011), to a group of proteins that curtail NF-κB when not cleaved by MALT1.…”

“…Its scaffold function marshals NF-κB activation, whereas proteolytic activity governs optimal proliferation and cytokine production (Bornancin et al, 2015;Gewies et al, 2014;Jaworski et al, 2014). MALT1 enzyme also regulates NF-κB signaling independently of the IKK complex by cleaving substrates including A20, RelB and MALT1 itself (Baens et al, 2014;Coornaert et al, 2008;Hailfinger et al, 2011). To explore the effect of HOIL1 cleavage on NF-κB activation, we first expressed HOIL1 or MALT1-resistant HOIL1 in Jurkat cells.…”

The Paracaspase MALT1

“…The study suggests that while the cleavage has no effect on the proteolytic activity of MALT1, the C-terminal cleavage fragment of 76 kDa can activate the expression of NF-κB target genes in a Bcl10-independent yet TRAF6-dependent manner. However, the cleavage site mutant does not affect phosphorylation of IκBα nor the relocalization of NF-κB subunits to the nucleus, and so the authors speculate that the C-terminal fragment exerts its effect on NF-κB signaling even further downstream after shuttling to the nucleus [108]. More work is needed to clarify this situation.…”

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

“…MALT1 can be auto-cleaved (Baens et al, 2014), but labeling with activity-based probes shows that MALT1 is active in its full length form Hachmann et al, 2015). Induction of catalytic activity involves conformational changes in the C-terminal Ig3 domain, which exerts an auto-inhibitory function but it is also essential for paracaspase activity (Wiesmann et al, 2012).…”

“…Interestingly, MALT1 itself and the constitutive binding partner BCL10 are cleaved upon TCR stimulation (Rebeaud et al, 2008;Baens et al, 2014). The function Figure 4: MALT1 protease supports optimal T cell activation.…”