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.
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.
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.
MALT1 has been shown to interact with BCL10,[14] TRAF6 and SQSTM1/p62.
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):
| Substrate | Reference | Cleavage sequence | |
|---|---|---|---|
| A20 (TNFAIP3) | [13] | LGASR/G | |
| BCL10 | [12] | LRSR/T | |
| CYLD | [15] | FMSR/G | |
| RELB | [16] | LVSR/G | |
| regnase-1/MCPIP1 (ZC3H12A) | [17] | LVPR/G | |
| Roquin-1 (RC3H1) | [18] | LIPR/G | |
| Roquin-2 (RC3H2) | [18] | LISR/S | |
| MALT1 auto-proteolysis | [19] | LCCR/A | |
| MALT1 auto-proteolysis | [20] | HCSR/T | |
| HOIL1 (RBCK1) | [21][22][23] | LQPR/G | |
| N4BP1 | [24] | FVSR/G | |
| CARD10 | [25] | LRCR/G | |
| ZC3H12D | [26] | LVPR/G | |
| ZC3H12B | [26] | LVPR/G | |
| TAB3 | [26] | LQSR/G | |
| CASP10 | [26] | LVSR/G | |
| CILK1 | [26] | LISR/S | |
| ILDR2 | [26] | GASR/G LVSR/T GASR/G | |
| TANK | [26] | HIPR/V | |
| Tensin-3 | [27] | R614, R645 |
Specifically by the oncogenic IAP2-MALT1 fusion:
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]
