Paracaspases (human: MALT1) are members of the C14 family of cysteine proteases.[1] Paracaspases are proteins related to caspases present in animals and slime mold, in contrast to metacaspases, which are present in plants, fungi, and "protists".[2] 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. Paracaspases are more similar to caspases than metacaspases are, indicating that this group of proteases diverged from caspases from a common metacaspase ancestor.
Most non-metazoan paracaspases found in amoebas or bacteria are "type 2" paracaspases with only a caspase-like domain. The animal paracaspases are most likely not directly related to the amoeba paracaspase.[3] It is currently unclear whether the paracaspases (and caspases) found in eukaryotes are a result from several (at least 2) independent horizontal gene transfer events from prokaryotes or if there has been a convergent evolution of (para)caspases evolved from the metacaspases in several different organisms within the eukaryotes.
The "type 2" paracaspases in animals represent the ancestral form which only consists of a caspase-like domain. This form of paracaspase can be found in ctenophora, trichoplax, sponges and cnidarians. Cnidarians also have "type 1" paracaspases.[3]
The "type 1" paracaspases are characterized by a MALT1-like domain composition with a death domain, immunoglobulin-like domains and a caspase-like domain. The "type 1" paracaspases first originated sometime before the last common ancestor of the bilaterans and cnidaria, indicating that "type 1" paracaspases originated during the ediacaran period.[3] The jawed vertebrates (starting from sharks) have 3 paralogs: PCASP1, PCASP2 and PCASP3. PCASP3 is the ancestral copy and can be found in all deuterostomes, like sea urchin, lancelets, tunicates and lampreys (a non-jawed vertebrate). Notably, mammals have lost PCASP2 and PCASP3 and only have PCASP1 (MALT1).[3] The non-deuterostome invertebrate type 1 paracaspase closest related to PCASP3 can surprisingly be found in molluscs, which could indicate that there were 2 paralog type 1 paracaspases present in the first bilaterans (like in cnidarians), and that different bilateran lineages have kept one or the other paralog.[4]
The paracaspase in Dictyostelium seems to regulate osmotic stress tolerance by vacuolar expansion.[5]
Paracaspase in animals has mostly been studied in humans and mice (see: MALT1), where it plays a major role in several pro-inflammatory pathways in innate- and adaptive- immunity. The distantly related zebrafish PCASP3 show conserved MALT1-like activity in NF-kappaB activation and protease substrate specificity, indicating that these functions were present in the last common ancestor of the three vertebrate paracaspase paralogs.[3]