MALT1

MALT1 paracaspase

PDB rendering based on 2g7r.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MALT1 ; IMD12; MLT; MLT1
External IDs OMIM: 604860 MGI: 2445027 HomoloGene: 4938 GeneCards: MALT1 Gene
EC number 3.4.22.-
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 10892 240354
Ensembl ENSG00000172175 ENSMUSG00000032688
UniProt Q9UDY8 Q2TBA3
RefSeq (mRNA) NM_006785 NM_172833
RefSeq (protein) NP_006776 NP_766421
Location (UCSC) Chr 18:
58.67 – 58.75 Mb		 Chr 18:
65.43 – 65.48 Mb
PubMed search

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the MALT1 gene.[1][2][3]

mucosa associated lymphoid tissue lymphoma translocation gene 1
Identifiers
Symbol MALT1
Alt. symbols MLT
Entrez 10892
HUGO 6819
OMIM 604860
RefSeq NM_173844
UniProt Q9UDY8
Other data
Locus Chr. 18 q21

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[4][5] Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.[6]

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.[7]

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.[8] 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.[9]

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,[10] 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:

Specifically by the oncogenic IAP2-MALT1 fusion:

See also

References

  1. ↑ Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P (June 1999). "The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas". Blood 93 (11): 3601–9. PMID 10339464.
  2. ↑ Hosaka S, Akamatsu T, Nakamura S, Kaneko T, Kitano K, Kiyosawa K, Ota H, Hosaka N, Miyabayashi H, Katsuyama T (July 1999). "Mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum with chromosomal translocation of the t(11;18)(q21;q21) and an additional aberration of trisomy 3". Am J Gastroenterol 94 (7): 1951–4. doi:10.1111/j.1572-0241.1999.01237.x. PMID 10406266.
  3. ↑ Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H, Ota H, Nakamura S, Morishima Y, Taniwaki M, Seto M (November 1999). "A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue". Oncogene 18 (42): 5785–94. doi:10.1038/sj.onc.1203018. PMID 10523859.
  4. ↑ Ruefli-Brasse AA, French DM, Dixit VM. (2003). "Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase". Science 28 (302): 1581–4. doi:10.1126/science.1090769. PMID 14576442.
  5. ↑ Ruland J, Duncan GS, Wakeham A, Mak TW. (2003). "Differential requirement for Malt1 in T and B cell antigen receptor signaling". Immunity 5 (19): 748–58. doi:10.1016/S1074-7613(03)00293-0. PMID 14614861.
  6. ↑ "Entrez Gene: MALT1 mucosa associated lymphoid tissue lymphoma translocation gene 1".
  7. ↑ Wegener E, Krappmann D. (2007). "CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB". Sci STKE. 381 (384): pe21. doi:10.1126/stke.3842007pe21. PMID 17473310.
  8. 1 2 Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D, Gaide O, Guzzardi M, Iancu EM, Rufer N, Fasel N, Thome M. (2008). "The proteolytic activity of the paracaspase MALT1 is key in T cell activation.". Nature Immunology 9 (3): 272–81. doi:10.1038/ni1568. PMID 18264101.
  9. 1 2 Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R. (2008). "T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20.". Nature Immunology 9 (3): 263–71. doi:10.1038/ni1561. PMID 18223652.
  10. ↑ Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM (October 2000). "Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma". Mol. Cell 6 (4): 961–7. doi:10.1016/S1097-2765(05)00086-9. PMID 11090634.
  11. ↑ Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P, Gevaert K, Beyaert R. (2011). "T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1.". EMBO J. 30 (4): 1742–52. doi:10.1038/emboj.2011.85. PMID 21448133.
  12. ↑ Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, Guzzardi M, Décaillet C, Grau M, Dörken B, Lenz P, Lenz G, Thome M. (2011). "Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines.". Proc Natl Acad Sci U S A. 108 (35): 14596–601. doi:10.1073/pnas.1105020108. PMID 21873235.
  13. ↑ Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K, Satoh T, Mino T, Suzuki Y, Standley DM, Tsujimura T, Rakugi H, Isaka Y, Takeuchi O, Akira S. (2013). "Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation.". Cell. 135 (5): 1036–49. doi:10.1016/j.cell.2013.04.034. PMID 23706741.
  14. ↑ Jeltsch KM, Hu D, Brenner S, Zöller J, Heinz GA, Nagel D, Vogel KU, Rehage N, Warth SC, Edelmann SL, Gloury R, Martin N, Lohs C, Lech M, Stehklein JE, Geerlof A, Kremmer E, Weber A, Anders HJ, Schmitz I, Schmidt-Supprian M, Fu M, Holtmann H, Krappmann D, Ruland J, Kallies A, Heikenwalder M, Heissmeyer V. (2014). "Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation.". Nat Immunol. 15 (11): 1079–89. doi:10.1038/ni.3008. PMID 25282160.
  15. ↑ Baens M, Bonsignore L, Somers R, Vanderheydt C, Weeks SD, Gunnarsson J, Nilsson E, Roth RG, Thome M, Marynen P. (2014). "MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.". PLOS ONE 9: e103774. doi:10.1371/journal.pone.0103774. PMID 25105596.
  16. ↑ Klein T, Fung SY, Renner F, Blank MA, Dufour A, Kang S, Bolger-Munro M, Scurll JM, Priatel JJ, Schweigler P, Melkko S, Gold MR, Viner RI, Régnier CH, Turvey SE, Overall CM. (2015). "The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling.". Nat Commun. doi:10.1038/ncomms9777. PMID 26525107.
  17. ↑ Elton L, Carpentier I, Staal J, Driege Y, Haegman M, Beyaert R (2015). "MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling.". FEBS J. doi:10.1111/febs.13597. PMID 26573773.
  18. ↑ Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A, Hamoudi RA, Noels H, Sagaert X, Van Loo P, Baens M, Du MQ, Lucas PC, McAllister-Lucas LM. (2011). "Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.". Science 331 (6016): 468–72. doi:10.1126/science.1198946. PMID 21273489.
  19. ↑ Nie Z, Du MQ, McAllister-Lucas LM, Lucas PC, Bailey NG, Hogaboam CM, Lim MS, Elenitoba-Johnson KS. (2015). "Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma.". Nat. Commun. 6 (5908). doi:10.1038/ncomms6908. PMID 25569716.

Further reading

  • Bertoni F, Cavalli F, Cotter FE, Zucca E (2003). "Genetic alterations underlying the pathogenesis of MALT lymphoma.". Hematol. J. 3 (1): 10–3. doi:10.1038/sj/thj/6200146. PMID 11960389. 
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