MALT1

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MALT1
Protein MALT1 PDB 2g7r.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMALT1, IMD12, MLT, MLT1, PCASP1, MALT1 paracaspase
External IDsOMIM: 604860 MGI: 2445027 HomoloGene: 4938 GeneCards: MALT1
Gene location (Human)
Chromosome 18 (human)
Chr.Chromosome 18 (human)[1]
Chromosome 18 (human)
Genomic location for MALT1
Genomic location for MALT1
Band18q21.32Start58,671,386 bp[1]
End58,754,477 bp[1]
RNA expression pattern
PBB GE MALT1 210018 x at fs.png

PBB GE MALT1 210017 at fs.png

PBB GE MALT1 208309 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 MbChr 18: 65.43 – 65.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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] It's the human paracaspase.

Function[edit]

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[edit]

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

Protease substrates[edit]

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:

Protease inhibitors[edit]

Since MALT1 protease activity is a promising therapeutic target, several different screenings have been performed which have resulted in different types of protease inhibitors.[27] There is active competition between multiple pharma companies and independent research groups in drug development against the MALT1 protease activity.

  • 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.[28]
  • Quinoline and thiazolopyridine allosteric MALT1 protease inhibitors have been demonstrated to work in mouse disease models. [34]
  • VIB is developing MALT1 protease inhibitors in collaboration with the Leuven-based spin-off Centre for Drug Design and Discovery (CD3) [38] [39]
  • Chordia therapeutics is entering a clinical trial with a MALT1 protease inhibitor in 2020 [41]

See also[edit]

References[edit]

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032688 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
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  6. ^ Hosaka S, Akamatsu T, Nakamura S, Kaneko T, Kitano K, Kiyosawa K, et al. (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.
  7. ^ Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H, et al. (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.
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  19. ^ 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 (8): e103774. doi:10.1371/journal.pone.0103774. PMC 4126661. PMID 25105596.
  20. ^ Ginster S, Bardet M, Unterreiner A, Malinverni C, Renner F, Lam S, et al. (2017). "Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation". PLOS ONE. 12 (1): e0169026. doi:10.1371/journal.pone.0169026. PMC 5214165. PMID 28052131.
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  24. ^ Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, et al. (May 2019). "N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation". Nature Microbiology. doi:10.1038/s41564-019-0460-3. PMID 31133753.
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  28. ^ Clinical trial number NCT03900598 for "A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)" at ClinicalTrials.gov
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  31. ^ Konczalla, Leonie; Perez, Daniel R.; Wenzel, Nadine; Wolters-Eisfeld, Gerrit; Klemp, Clarissa; Lüddeke, Johanna; Wolski, Annika; Landschulze, Dirk; Meier, Chris; Buchholz, Anika; Yao, Dichao; Hofmann, Bianca T.; Graß, Julia K.; Spriestersbach, Sarah L.; Grupp, Katharina; Schumacher, Udo; Betzel, Christian; Kapis, Svetlana; Nuguid, Theresa; Steinberg, Pablo; Püschel, Klaus; Sauter, Guido; Bockhorn, Maximillian; Uzunoglu, Faik G.; Izbicki, Jakob R.; Güngör, Cenap; El Gammal, Alexander T. (2019-07-10). "Biperiden and Mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer". International Journal of Cancer. doi:10.1002/ijc.32567. ISSN 1097-0215. PMID 31291468.
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  39. ^ "VIB, CD3 and Galapagos NV enter license deal for the development of MALT1 inhibitors". Science|Business. Retrieved 2019-05-31.
  40. ^ "India's first-in-class MALT1 blocker deal" (News). Nature Biotechnology. 2019-02-04. Retrieved 2019-05-31.
  41. ^ "Chordia Therapeutics Raises Approximately 27 million USD in Series B Financing" (PDF). 2019-03-29. Retrieved 2019-05-31.

Further reading[edit]

  • 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.