MALT1

Detailed Information

MALT1 (Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1) is a gene located on chromosome 18q21. It encodes a cysteine protease (paracaspase) structurally related to the caspase superfamily but functionally distinct from apoptosis-related caspases in terms of substrate specificity and biological role. The gene comprises multiple exons and undergoes alternative splicing, resulting in several transcript variants with subtle differences in tissue distribution and functional regulation.

The MALT1 protein possesses characteristic domains, including an N-terminal death domain, immunoglobulin-like domains, and a C-terminal caspase-like domain containing key residues essential for catalytic activity. MALT1 functions not as an isolated entity but as a core component of the CARMA1–BCL10–MALT1 (CBM) signaling complex, which plays a central role in antigen receptor-mediated lymphocyte activation. Upon stimulation of T-cell receptors (TCRs) or B-cell receptors (BCRs), CARMA1 recruits BCL10 and MALT1 via its CARD domain, assembling a functional signal transduction platform. This platform activates downstream NF-κB and MAPK signaling pathways, thereby promoting lymphocyte proliferation, differentiation, and production of pro-inflammatory cytokines.

Figure 1. NF-κB and JNK activation by the CBM complex. (Meininger I, et al., 2016)

Biological Function and Molecular Mechanisms

MALT1 serves dual functions in the immune system: as a scaffold protein assembling signaling complexes and as a protease that cleaves specific substrates. As a scaffold, MALT1 binds BCL10 via its N-terminal domain and recruits the E3 ubiquitin ligase TRAF6 via its C-terminal domain, activating the IKK complex (IκB kinase). IKK phosphorylates IκBα, leading to its proteasomal degradation and the nuclear translocation of NF-κB transcription factors—an essential cascade for lymphocyte activation and inflammatory responses.

Recent studies have emphasized the indispensability of MALT1's proteolytic activity in immune regulation. Upon antigen stimulation, MALT1 cleaves various regulatory proteins such as BCL10, A20 (TNFAIP3), Regnase-1, and Roquin family members. For instance, Regnase-1 is a negative regulator of mRNA stability that degrades transcripts encoding inflammatory cytokines. MALT1-mediated cleavage of Regnase-1 inactivates its function, thereby stabilizing mRNAs like IL-2, IL-6, and TNF-α, amplifying the inflammatory response.

Figure 2. MALT1 protease supports optimal T cell activation. (Meininger I, et al., 2016)

A novel mechanism in psoriasis pathogenesis involves a keratinocyte-specific splice variant, CARD14sh, which forms a CBM complex with BCL10 and MALT1. This complex orchestrates antiviral responses via dual mechanisms: activating NF-κB to induce inflammatory cytokines and, simultaneously, MALT1 cleaves the mitochondrial antiviral signaling protein MAVS at residue R384. This results in a ~50 kDa MAVS fragment and its K48-linked polyubiquitination, targeting it for proteasomal degradation. This cleavage suppresses MAVS-mediated IRF3 activation and type I interferon production. Notably, psoriasis-associated CARD14 mutants (e.g., E138A/E142G) show impaired IRF3 suppression, leading to excessive interferon signaling, which contributes to the disease's interferon-rich signature. This finely tuned balance enables effective antiviral defense while preventing excessive inflammatory damage in skin tissues.

Clinical Relevance and Disease Associations

Dysregulated activation of MALT1 has been implicated in multiple diseases, most notably lymphomas and primary immunodeficiencies:

Mucosa-Associated Lymphoid Tissue Lymphoma (MALT Lymphoma)

The hallmark genetic abnormality is a chromosomal translocation, particularly t(11;18)(q21;q21), leading to the BIRC3–MALT1 fusion gene (found in ~30–40% of cases). The fusion protein combines the N-terminal apoptosis-inhibitory domain of BIRC3 with the C-terminal catalytic domain of MALT1, enabling constitutive oligomerization and NF-κB activation independent of CBM complex formation. Interestingly, there is a mutually exclusive relationship between Helicobacter pylori (HP) infection and MALT1 translocation—HP-positive cases rarely exhibit the translocation (~7.5%), while HP-negative cases show significantly higher rates. Studies indicate that MALT1-translocated lymphomas display a distinct immune microenvironment, such as significantly reduced infiltration of CD56+ natural killer (NK) cells, suggesting impaired innate immune surveillance. Moreover, MALT1 mRNA expression is markedly elevated in Diffuse Large B-Cell Lymphoma (DLBCL) compared to MALT lymphoma and correlates with lymph node metastasis, advanced clinical stage (III–IV), and poor prognosis.

Primary Immunodeficiency (IMD12)

In contrast to the gain-of-function mutations seen in lymphomas, loss-of-function mutations in MALT1 result in the autosomal recessive disorder IMD12. Patients exhibit recurrent bacterial, viral, and fungal infections, accompanied by defective T-cell proliferation and impaired Th17 cell differentiation. Mechanistically, these mutations impair either MALT1's protease activity or its scaffold function, hindering TCR-mediated NF-κB activation and significantly reducing cytokine production such as IL-2 and IL-17.

Chronic Inflammatory Diseases

Beyond psoriasis, MALT1 hyperactivation has been implicated in autoimmune diseases like rheumatoid arthritis and multiple sclerosis. In Chronic Obstructive Pulmonary Disease (COPD), a 2024 study reported that elderly patients in acute exacerbation stages show elevated blood MALT1 levels, which inversely correlate with lung function indices and positively correlate with GOLD staging. This suggests MALT1 as a potential biomarker for acute COPD exacerbations.

Table: MALT1-Associated Diseases and Molecular Mechanisms

Targeted Therapeutic Strategies and Future Directions

Given its pivotal role in diverse diseases, MALT1 is a promising therapeutic target. Current strategies focus on:

• Protease-Specific Inhibitors: Small molecules such as Mepazine and Z-VRPR-fmk selectively inhibit MALT1's protease activity without affecting its scaffold function. In psoriasis models, Mepazine inhibits MAVS cleavage, enhancing antiviral responses while mitigating inflammation. However, such inhibitors may interfere with physiological immune surveillance and increase infection or tumor risk.
• Proteolysis-Targeting Chimeras (PROTACs): These bifunctional molecules recruit an E3 ubiquitin ligase to MALT1, inducing its selective degradation. This approach has shown promising efficacy in relapsed/refractory lymphoma models.
• Allosteric Modulators: Designed to disrupt the interaction between MALT1's immunoglobulin-like domains and its partners (BCL10 or TRAF6), these inhibitors could block CBM complex assembly with higher specificityand potentially lower off-target effects.

Preclinical studies show that MALT1 inhibitors significantly suppress tumor growth in xenograft lymphoma models and enhance the efficacy of PD-1 inhibitors. Nevertheless, excessive immune suppression remains a concern in the context of autoimmune diseases. Future research may focus on tissue-specific delivery systems(e.g., skin-targeted nanoparticles for psoriasis) and combination therapies (e.g., MALT1 and BTK inhibitors in B-cell lymphomas).

MALT1 represents a critical molecular node bridging innate and adaptive immunity. Its functional complexity—balancing enzymatic activity and scaffold assembly—presents both challenges and opportunities for therapeutic intervention. As structural and network-level understanding of the CBM complex deepens, disease-tailored strategies targeting MALT1 may yield transformative clinical advances.