Paracaspase

Paracaspases (human: MALT1) are proteins related to caspases present in animals and slime mold, in contrast to metacaspases, which are present in plants, fungi, and "protists".^[1]

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 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^[2][3]

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.^[4]

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.^[5] 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 an inhibitor of NF-κB, this suggests that paracaspase-mediated A20 cleavage in T lymphocytes is necessary for a proper NF-κB activation.^[6]

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.

See also

• The Proteolysis Map
• Malt1
• Caspase
• Metacaspase
• MALT lymphoma

References

1. ^ Uren A, O'Rourke K, Aravind L, Pisabarro M, Seshagiri S, Koonin E, Dixit V (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. 
2. ^ 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. 
3. ^ 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. 
4. ^ 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. 
5. ^ 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. 
6. ^ 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.