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Ways and waves of MALT1 paracaspase activation

Cellular & Molecular Immunology volume 15, pages 8–11 (2018)Cite this article

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), also known as paracaspase 1, is a ubiquitous protease with homology to caspases.1 The function of MALT1 is best understood in immune cells, in particular lymphocytes, in which MALT1 controls signaling downstream of antigen receptors, for example, nuclear-factor-kappa-B (NF-κB) and mitogen-activated protein kinase pathways. Activation of MALT1 paracaspase activity has been shown to require the assembly of a tripartite signaling complex termed CBM (CARD11/BCL10/MALT1), which is formed following the phosphorylation and conformational change of caspase recruitment domain 11 (CARD11) that is induced by antigen-receptor stimulation. This complex then recruits the E3 ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of the inhibitor-of-kappa-B kinase (IκK) complex, an essential step in the release of transcriptionally active NF-κB. Now, according to recent studies, there might be alternative mechanisms for MALT1 activation that do not rely on the recruitment into CBM complexes. In the first study, Li and colleagues show that the OX40 signaling pathway in invariant natural killer T (iNKT) cells activates caspase-1 by recruiting MALT1 in a TRAF6-dependent manner that might bypass CBM formation.2 In the second study, Thome and colleagues show that two Kaposi’s sarcoma-associated herpes virus (KSHV) proteins promote NF-κB activation via binding to MALT1 and activating its paracaspase activity, likely in a CBM-independent manner.3 These findings are highlighted below and show how emerging concepts continue to push the current boundaries of our understanding of the function of MALT1.

The recent work by Li and colleagues, published in the June issue of The Journal of Clinical Investigation,2 showed that OX40, a TNF superfamily receptor (TNFRSF4), can activate the MALT1 protease in iNKT cells. Although normally associated with T-cell survival, effector differentiation and memory generation, this study uncovered that OX40 signaling in iNKT cells instead leads to caspase-1-dependent programmed cell death, also known as pyroptosis. Furthermore, in TRAF6-deficient iNKT cells, OX40 failed to induce caspase-1 activation, as shown by the absence of caspase-1 cleavage using immunoblotting and flow cytometry methods. Next, using an immunoprecipitation approach with FACS-sorted iNKT cells stimulated with OX40 ligand in vitro, the authors identified BCL10 and MALT1 as TRAF6 interactors. By overexpressing TRAF6, MALT1 and caspase-1 in 293T cells, they observed that TRAF6 fails to co-immunoprecipitate with caspase-1 in the absence of MALT1, suggesting that MALT1 is a critical component for TRAF6-mediated activation of caspase-1. Binding of BCL10 to MALT1 also appears to be key because deletion of the N-terminal region of MALT1—a region previously shown to contain key determinants of BCL10 binding—abrogated recruitment of caspase-1 into the MALT1-TRAF6 complex. Additionally, a MALT1 protease inhibitor could block the cleavage of caspase-1 in a concentration-dependent manner, thus suggesting the involvement of MALT1 paracaspase activity in caspase-1 activation. Collectively, these data suggested that in iNKT cells, activation of the OX40 pathway recruits MALT1-BCL10 through TRAF6, and MALT1 then activates caspase-1 to induce cellular pyroptosis. Whether cleavage of caspase-1 is directly performed by MALT1 or if there is an intermediate regulator, however, remains to be clarified.

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Acknowledgements

The authors thank Christopher Farady for his critical reading of the manuscript.

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  1. Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4002, Switzerland

    Laura Israël & Frédéric Bornancin

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  1. Laura Israël
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Correspondence to Frédéric Bornancin.

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Israël, L., Bornancin, F. Ways and waves of MALT1 paracaspase activation. Cell Mol Immunol 15, 8–11 (2018). https://doi.org/10.1038/cmi.2017.77

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