Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (MALT1)

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a unique cysteine protease and a critical component of the CARD11-BCL10-MALT1 (CBM) signaling complex (UniProt: Q9UDY8). It plays a dual role in immune cell activation: acting as a structural scaffold for the assembly of signaling complexes and as an enzyme (paracaspase) that cleaves specific substrates like BCL10, CYLD, and RelB to sustain NF-kappaB pathway activation (PubMed: 32814544). MALT1 is frequently dysregulated in various B-cell lymphomas, such as MALT lymphoma and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), where its constitutive activity drives tumor cell survival and proliferation (Wikipedia: MALT1). Consequently, the paracaspase domain of MALT1 has emerged as a significant therapeutic target, with small-molecule inhibitors like Safitanyir being developed to block its proteolytic function and suppress oncogenic signaling (ClinicalTrials.gov: NCT03900715). Beyond oncology, MALT1 inhibition is also being explored for the treatment of autoimmune and inflammatory disorders due to its central role in T-cell and B-cell receptor signaling (PubMed: 28219142). Therapeutic strategies include both active-site inhibitors and allosteric modulators that stabilize the protease in an inactive conformation. Clinical trials are currently evaluating the safety and efficacy of these inhibitors in patients with relapsed or refractory B-cell malignancies. Monitoring the cleavage products of MALT1 substrates serves as a key pharmacodynamic biomarker in these studies.

Other names

ParacaspaseMLTMLT1IMD80MALT1 paracaspase domainCaspase-like protein

Inhibition of the paracaspase proteolytic activity through either active-site binding or allosteric modulation, preventing the cleavage of negative regulators of NF-kappaB signaling (PubMed: 22544325).