Paracaspase
Encyclopedia
Paracaspases are related to caspases present in animals and slime mold, in contrast to metacaspase
s, which are present in plants, fungi, and "protists".
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
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.
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. 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.
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.
Metacaspase
Metacaspases are related to caspases and paracaspase. The metacaspases are Arginine/Lysine-specific, in contrast to caspases, which are Aspartate-specific...
s, which are present in plants, fungi, and "protists".
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
MALT lymphoma
MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue , frequently of the stomach, but virtually any mucosal site can be afflicted...
. 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
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.
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
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
464 and histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
414 are crucial for this activity. Like metacaspases, the paracaspase cleaves substrates after an arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
residue. To date, two paracaspase substrates have been described. Bcl-10 is cut after arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
228. This removes the last five amino acids at the C-terminus and is crucial for T cell adhesion to fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, 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. A20
A20
A20, A 20, A.20 or A-20 may refer to:* A20 line, a microprocessor connection* British NVC community A20 , a plant community-Vehicles:* A-20 Havoc, a U.S.-designed attack aircraft used in World War II...
, 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.
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 MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
- Malt1MALT1Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the MALT1 gene.-Further reading:...
- CaspaseCaspaseCaspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
- MetacaspaseMetacaspaseMetacaspases are related to caspases and paracaspase. The metacaspases are Arginine/Lysine-specific, in contrast to caspases, which are Aspartate-specific...
- MALT lymphomaMALT lymphomaMALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue , frequently of the stomach, but virtually any mucosal site can be afflicted...