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Genetic ablation of the paracaspase gene is mice and biochemical studies have shown that Malt1 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<ref>{{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}}</ref><ref>{{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}} </ref>
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<ref>{{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}}</ref><ref>{{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}} </ref>




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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.
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 throught 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<ref>{{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=Epub ahead of print |year=2008 |pmid=18264101}}</ref>. A20, a deubiquitine ligase, has been shown to be cut by Malt1 in Human and in mouse. An uncleavable A20 mutant is still capable to activate [[NF-κB]], but the [[C-terminal]] or the [[N-terminal]] A20 cleavage products activates more [[NF-κB]] than wild-type A20 does. 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.<ref> {{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=Epub ahaed of print |year=2008 |pmid=18223652 }}</ref>
Paracaspase has been show to have [[proteolytic]] activity throught 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<ref>{{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=Epub ahead of print |year=2008 |pmid=18264101}}</ref>. A20, a deubiquitine ligase, has been shown to be cut by paracaspase in Human and in mouse. An uncleavable A20 mutant is still capable to activate [[NF-κB]], but the [[C-terminal]] or the [[N-terminal]] A20 cleavage products activates more [[NF-κB]] than wild-type A20 does. 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.<ref> {{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=Epub ahaed of print |year=2008 |pmid=18223652 }}</ref>


By targetting paracaspase proteolytic activity, it might be possible to develop new drugs that might be useful for the treatment of certains [[lymphomas]] or [[autoimmune]] disorders.
By targetting paracaspase proteolytic activity, it might be possible to develop new drugs that might be useful for the treatment of certains [[lymphomas]] or [[autoimmune]] disorders.
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* Malt1
* Malt1
* Caspase
* Metacaspase




Revision as of 20:37, 19 February 2008

mucosa associated lymphoid tissue lymphoma translocation gene 1
Identifiers
SymbolMALT1
Alt. symbolsMLT
NCBI gene10892
HGNC6819
OMIM604860
RefSeqNM_173844
UniProtQ9UDY8
Other data
LocusChr. 18 q21
Search for
StructuresSwiss-model
DomainsInterPro

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".[1]

Paracaspases are more similar to caspases than metacaspases are, indicating that this group of (putative) 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.


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[2][3]


In addition, a role for paracaspase has been shown in the innate immunes response mediated by the zymosan receptor Dectin-1 in macrophages and dendritic cells, and in response to the 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 throught 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. An uncleavable A20 mutant is still capable to activate NF-κB, but the C-terminal or the N-terminal A20 cleavage products activates more NF-κB than wild-type A20 does. 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.[6]

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


See also

  • Malt1
  • Caspase
  • Metacaspase


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. PMID 11090634.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. PMID 14576442. {{cite journal}}: Cite has empty unknown parameter: |1= (help)CS1 maint: multiple names: authors list (link)
  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. PMID 14614861.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Wegener E, Krappmann D. (2007). "CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB". Sci STKE. 381. 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. Epub ahead of print. PMID 18264101.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. Epub ahaed of print. PMID 18223652.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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