MALT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2G7R, 3BFO, 3K0W, 3UO8, 3UOA, 3V4O, 3V55, 4I1P, 4I1R
Identifiers
Aliases	MALT1, IMD12, MLT, MLT1, PCASP1, MALT1 paracaspase
External IDs	OMIM: 604860 MGI: 2445027 HomoloGene: 4938 GeneCards: MALT1
Gene location ( Human) Chr. Chromosome 18 (human) [1] Band 18q21.32 Start 58,671,465 bp [1] End 58,754,477 bp [1]
Gene location ( Mouse) Chr. Chromosome 18 (mouse) [2] Band 18|18 E1 Start 65,564,009 bp [2] End 65,612,138 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in thymus Achilles tendon monocyte lymph node appendix stromal cell of endometrium prostate parotid gland bone marrow cells gastrocnemius muscle Top expressed in spleen blood subcutaneous adipose tissue interventricular septum parotid gland seminal vesicula spermatid white adipose tissue spermatocyte lens More reference expression data BioGPS More reference expression data
Gene ontology Molecular function signal transducer activity ubiquitin-protein transferase activity protease binding protein self-association peptidase activity protein binding kinase activator activity cysteine-type endopeptidase activity hydrolase activity identical protein binding Cellular component cytoplasm plasma membrane nucleolus perinuclear region of cytoplasm nucleus fibrillar center cytosol CBM complex Biological process regulation of apoptotic process defense response regulation of T cell receptor signaling pathway negative regulation of apoptotic process stimulatory C-type lectin receptor signaling pathway activation of NF-kappaB-inducing kinase activity proteolysis Fc-epsilon receptor signaling pathway T cell proliferation B cell activation response to fungus positive regulation of T cell activation positive regulation of interleukin-2 production protein complex oligomerization positive regulation of T cell cytokine production positive regulation of I-kappaB kinase/NF-kappaB signaling nuclear export B-1 B cell differentiation response to molecule of bacterial origin positive regulation of protein ubiquitination T cell receptor signaling pathway protein ubiquitination innate immune response positive regulation of NF-kappaB transcription factor activity Sources: Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10892 240354 Ensembl ENSG00000172175 ENSMUSG00000032688 UniProt Q9UDY8 Q2TBA3 RefSeq (mRNA) NM_006785 NM_173844 NM_172833 NM_001365019 RefSeq (protein) NP_006776 NP_776216 NP_766421 NP_001351948 Location (UCSC) Chr 18: 58.67 – 58.75 Mb Chr 18: 65.56 – 65.61 Mb PubMed search [3] [4]
Wikidata
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Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the MALT1 gene. ^{[5] [6] [7]} It's the human paracaspase.

Function

Genetic ablation of the paracaspase gene in mice and biochemical studies have shown that paracaspase is a crucial protein for T and B lymphocytes activation. It has an important role in the activation of the transcription factor NF-κB, in the production of interleukin-2 (IL-2) and in T and B lymphocytes proliferation ^{[8] [9]} Two alternatively spliced transcript variants encoding different isoforms have been described for this gene. ^[10]

In addition, a role for paracaspase has been shown in the innate immune response mediated by the zymosan receptor Dectin-1 in macrophages and dendritic cells, and in response to the stimulation of certain G protein-coupled receptors. ^[11]

Sequence analysis proposes that paracaspase has an N-terminal death domain, two central immunoglobulin-like domains involved in the binding to the B-cell lymphoma 10 (Bcl10) protein and a caspase-like domain. The death domain and immunoglobulin-like domains participate in binding to BCL10. Activation of MALT1 downstream NF-κB signaling and protease activity occurs when BCL10/MALT1 gets recruited to an activated CARD-CC family protein ( CARD9, -10, -11 or -14) in a so-called CBM (CARD-CC/BCL10/MALT1) signaling complex.

Paracaspase has been shown to have proteolytic activity through its caspase-like domain in T lymphocytes. Cysteine 464 and histidine 414 are crucial for this activity. Like metacaspases, the paracaspase cleaves substrates after an arginine residue. To date, several paracaspase substrates have been described (see below). Bcl10 is cut after arginine 228. This removes the last five amino acids at the C-terminus and is crucial for T cell adhesion to fibronectin, but not for NF-κB activation and IL-2 production. However, using a peptide-based inhibitor (z-VRPR-fmk) of the paracaspase proteolytic activity, it has been shown that this activity is required for a sustain NF-κB activation and IL-2 production, suggesting that paracaspase may have others substrates involved in T cell-mediated NF-κB activation. ^[12] A20, a deubiquitinase, has been shown to be cut by paracaspase in Human and in mouse. Cells expressing an uncleavable A20 mutant is however still capable to activate NF-κB, but cells expressing the C-terminal or the N-terminal A20 cleavage products activates more NF-κB than cells expressing wild-type A20, indicating that cleavage of A20 leads to its inactivation. Since A20 has been described has an inhibitor of NF-κB, this suggests that paracaspase-mediated A20 cleavage in T lymphocytes is necessary for a proper NF-κB activation. ^[13]

By targeting paracaspase proteolytic activity, it might be possible to develop new drugs that might be useful for the treatment of certain lymphomas or autoimmune disorders.

Interactions

MALT1 has been shown to interact with BCL10, ^[14] TRAF6 and SQSTM1/p62.

Protease substrates

MALT1 (PCASP1) is part of the paracaspase family and shows proteolytic activity. Since many of the substrates are involved in regulation of inflammatory responses, the protease activity of MALT1 has emerged as an interesting therapeutic target. Currently known protease substrates are (in order of reported discovery):

Specifically by the oncogenic IAP2-MALT1 fusion:

• NIK ^[28]
• LIMA1 ^[29]

Protease inhibitors

Since MALT1 protease activity is a promising therapeutic target, several different screenings have been performed which have resulted in different types of protease inhibitors. ^[30] There is active competition between multiple pharma companies and independent research groups in drug development against the MALT1 protease activity. ^[31]

• Substrate peptide-based active-site inhibitor: Initially described with the metacaspase inhibitor VRPR-fmk. ^[12] Others have developed peptide inhibitors based on the optimal peptide sequence (LVSR) or further chemical modifications. Janssen Pharmaceutica is currently performing a clinical trial with this class of inhibitors. ^[32]
• Phenothiazine compounds like mepazine and chlorpromazine (which have been used clinically for neurological/psychological conditions) have been found to be allosteric inhibitors of MALT1 protease activity. ^{[33] [34]}
• Biperiden, like phenothiazines, act as a MALT1 protease inhibitor and show promising results against pancreatic cancer. ^[35]
• A molecular modeling approach led to the development of the small molecule active site inhibitor MI-2. ^[36]
• Analogs of β-Lapachone have been identified as MALT1 protease inhibitors. ^[37]
• Quinoline and thiazolopyridine allosteric MALT1 protease inhibitors have been demonstrated to work in mouse disease models. ^[38]
• secondary metabolites (oxepinochromenones) from the fungus Dictyosporium show MALT1 protease inhibitory activity. ^[39]
• Novartis is developing pyrazolopyrimidine derivative MALT1 protease inhibitors. ^{[40] [41]}
• VIB is developing MALT1 protease inhibitors in collaboration with the Leuven-based spin-off Centre for Drug Design and Discovery (CD3) ^{[42] [43]}
• AstraZeneca is developing MALT1 protease inhibitors. ^{[42] [44]}
• Lupin and AbbVie are developing MALT1 protease inhibitors. ^[45]
• Chordia therapeutics is entering a clinical trial with a MALT1 protease inhibitor in 2020 ^[46]
• In the "First Time Disclosure Session" at 2024 ACS conference. Schrödinger announced the discovery of their SGR-1505 innhibitor. ^{[47] [48]}

See also

• Paracaspase

References

Further reading

External links

• Overview of all the structural information available in the PDB for UniProt: Q9UDY8 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) at the PDBe-KB.