MALT1 Proteolytic Signaling in Immune Responses

MALT1 proteolytic signalling serves as a central node in antigen receptor–mediated activation of both innate and adaptive immune responses. As a dual-function paracaspase within the CARD11–BCL10–MALT1 (CBM) signalosome, MALT1 orchestrates NF-κB activation by acting as a scaffold to recruit ubiquitin ligases and as a protease to cleave negative regulators of signalling. Upon engagement of T or B cell receptors, CBM assembly triggers MALT1 protease activity, leading to the cleavage of substrates such as A20, RelB, CYLD and HOIL1. This potentiates canonical NF-κB signalling by removing inhibitory checkpoints and fine-tuning the amplitude and duration of the response. MALT1 also participates in the differentiation and suppressive function of regulatory T cells, maintaining immune homeostasis by modulating cytokine production and checkpoint expression. Dysregulated MALT1 activity has been implicated in lymphoid malignancies, autoimmunity and immune-suppressive tumour microenvironments. Recent advances have revealed mechanisms that govern alternative splicing of MALT1, auto-proteolysis and linear ubiquitin feedback loops, underscoring its role as both a positive driver and a negative terminator of NF-κB signalling. The growing understanding of MALT1-dependent proteolysis has opened avenues for selective therapeutic inhibition to treat lymphomas, autoimmune disorders and to enhance anti-tumour immunity.

Research from Nature Portfolio

Recent studies have extended the mechanistic framework of MALT1 proteolysis. Proteomic analyses of patient-derived B cells have identified the linear ubiquitin assembly complex component HOIL1 as a novel MALT1 substrate, revealing that cleavage of HOIL1 attenuates linear ubiquitination of key NF-κB regulators and enforces a negative-feedback loop to terminate signalling. Investigations into MALT1 transcript variants have shown that alternative splicing generates MALT1A and MALT1B isoforms, with inclusion of the exon encoding the TRAF6-binding motif selectively enhancing MALT1 scaffolding and NF-κB activation in stimulated T cells. Furthermore, dissection of CBM-dependent regulatory T cell biology has demonstrated that MALT1 protease activity is indispensable for Treg suppressive function, and that its acute inhibition in the tumour microenvironment potentiates anti-tumour immune responses without impairing differentiation.

MALT1 Proteolytic Signaling in Immune Responses publication trend

The graph below shows the total number of articles in malt1 proteolytic signaling in immune responses across all publications each year (not limited to Nature Index journals).

Technical terms

MALT1 protease: A paracaspase enzyme within the CBM complex that cleaves signalling inhibitors to regulate NF-κB activation.

CBM complex: The CARD11–BCL10–MALT1 signalosome that bridges antigen receptor engagement to downstream transcriptional programmes.

NF-κB: A family of transcription factors central to the regulation of inflammatory and immune-response genes.

Ubiquitination: A post-translational modification involving attachment of ubiquitin chains to substrates, modulating degradation and signalling.

Regulatory T cells (Tregs): A specialised subset of T lymphocytes that suppress immune responses and maintain tolerance.

Paracaspase: A protease related to caspases, combining scaffold and enzymatic functions in immune signalling complexes.

References

1. Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma. Journal of Clinical Investigation (2023).
2. Function and targeting of MALT1 paracaspase in cancer. Cancer Treatment Reviews (2023).
3. MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas. Blood Cancer Journal (2023).
4. The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling. Nature Communications (2015).
5. MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses. PLOS ONE (2015).
6. MALT1 Auto-Proteolysis Is Essential for NF-κB-Dependent Gene Transcription in Activated Lymphocytes. PLOS ONE (2014).
7. Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells. Nature Communications (2016).
8. Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells. Nature Communications (2019).