MALT1

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	MGI: 2445027 HomoloGene: 4938 GeneCards: MALT1
Gene location (Human) Chr. Chromosome 18 (human)[1] Band No data available Start 58,671,386 bp[1] End 58,754,477 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band No data available Start 65,430,963 bp[2] End 65,478,823 bp[2]
RNA expression pattern 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 Cellular component • cytoplasm • plasma membrane • protein complex • nucleolus • perinuclear region of cytoplasm • nucleus • CBM complex • fibrillar center • cytosol 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 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
RefSeq (protein)	NP_006776 NP_776216	NP_766421
Location (UCSC)	Chr 18: 58.67 – 58.75 Mb	Chr 18: 65.43 – 65.48 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the MALT1 gene.^[5][6][7]

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 a 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.

Paracaspase has been show 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:

• TNFAIP3 (A20) ^[13]
• BCL10 ^[12]
• CYLD ^[15]
• RELB ^[16]
• regnase-1 (MCPIP1) ^[17]
• Roquin-1 and -2 ^[18]
• MALT1 auto-proteolysis ^[19]
• HOIL1 ^[20][21]

Specifically by the oncogenic IAP2-MALT1 fusion:

• NIK ^[22]
• LIMA1 ^[23]

See also

• Paracaspase

References

Further reading