Name= mucosa associated lymphoid tissue lymphoma translocation gene 1


Paracaspases (human: MALT1) are related to caspases present in animals and slime mold, in contrast to metacaspases, which are present in plants, fungi, and "protists". [cite journal |author=Uren A, O'Rourke K, Aravind L, Pisabarro M, Seshagiri S, Koonin E, Dixit V |title=Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma |journal=Mol Cell |volume=6 |issue=4 |pages=961–7 |year=2000 |pmid=11090634]

Paracaspases are more similar to caspases than metacaspases are, indicating that this group of proteases diverged from caspases from a common metacaspase ancestor. The phylogenetic distribution is a bit confusing, since slime mold diverged earlier than the animal/fungal split.

Paracaspase has been first identified in a recurrent t(11;18)(q21;q21) chromosomal translocation associated with a subset of MALT lymphoma. This leads to a fusion oncoprotein consisting of the carboxyl terminus of MALT1 and the amino terminus of c-IAP2.

Genetic ablation of the paracaspase gene is mice and biochemical studies have shown that paracaspase is a crucial protein for T and B lymphocytes activation. It has a 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 [cite journal | author=Ruefli-Brasse AA, French DM, Dixit VM.|title=Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase |journal=Science | volume=28 | issue=302|pages=1581–4 |year=2003 |pmid=14576442|doi=10.1126/science.1090769] [cite journal | author=Ruland J, Duncan GS, Wakeham A, Mak TW. |title=Differential requirement for Malt1 in T and B cell antigen receptor signaling |journal=Immunity |volume=5 |issue=19 |pages=748–58 |year=2003 |pmid=14614861 ]

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. [cite journal |author=Wegener E, Krappmann D. |title=CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB |journal=Sci STKE. |volume=381 |year=2007 |pmid=17473310]

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 (Bcl-10) 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, two paracaspase substrates have been described. Bcl-10] 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 [cite journal |author=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. |title=The proteolytic activity of the paracaspase MALT1 is key in T cell activation. |journal=Nature Immunology |volume=9 |year=2008 |pmid=18264101 |doi=10.1038/ni1568 |pages=272] . A20, a deubiquitine ligase, 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 a inhibitor of NF-κB, this suggests that paracaspase-mediated A20 cleavage in T lymphocytes is necessary for a proper NF-κB activation. [ cite journal |author=Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R. |title=T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. |journal=Nature Immunology |volume=9 |year=2008 |pmid=18223652 |doi=10.1038/ni1561 |pages=263 ]

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

ee also

* Malt1
* Caspase
* Metacaspase
* MALT lymphoma


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