PT - JOURNAL ARTICLE AU - Jens Staal AU - Yasmine Driege AU - Alice Borghi AU - Paco Hulpiau AU - Laurens Lievens AU - Ismail Sahin Gul AU - Srividhya Sundararaman AU - Amanda Gonçalves AU - Ineke Dhondt AU - Bart P. Braeckman AU - Ulrich Technau AU - Yvan Saeys AU - Frans van Roy AU - Rudi Beyaert TI - The CARD-CC/Bcl10/paracaspase signaling complex is functionally conserved since the last common ancestor of Planulozoa AID - 10.1101/046789 DP - 2016 Jan 01 TA - bioRxiv PG - 046789 4099 - http://biorxiv.org/content/early/2016/12/29/046789.short 4100 - http://biorxiv.org/content/early/2016/12/29/046789.full AB - Type 1 paracaspases originated in the Ediacaran geological period before the last common ancestor of bilaterians and cnidarians (Planulozoa). Cnidarians have several paralog type 1 paracaspases, type 2 paracaspases, and a homolog of Bcl10. Notably in bilaterians, lineages like nematodes and insects lack Bcl10 whereas other lineages such as vertebrates, hemichordates, annelids and mollusks have a Bcl10 homolog. A survey of invertebrate CARD-coiled-coil (CC) domain homologs of CARMA/CARD9 revealed such homologs only in species with Bcl10, indicating an ancient co-evolution of the entire CARD-CC/Bcl10/MALT1-like paracaspase (CBM) complex. Furthermore, vertebrate-like Syk/Zap70 tyrosine kinase homologs with the ITAM-binding SH2 domain were found in invertebrate organisms with CARD-CC/Bcl10, indicating that this pathway might be the original user of the CBM complex. We also established that the downstream signaling proteins TRAF2 and TRAF6 are functionally conserved in Cnidaria. There also seems to be a correlation where invertebrates with CARD-CC and Bcl10 have type 1 paracaspases which are more similar to the paracaspases found in vertebrates. A proposed evolutionary scenario includes at least two ancestral type 1 paracaspase paralogs in the planulozoan last common ancestor, where at least one paralog usually is dependent on CARD-CC/Bcl10 for its function. Functional analyses of invertebrate type 1 paracaspases and Bcl10 homologs support this scenario and indicate an ancient origin of the CARD-CC/Bcl10/paracaspase signaling complex. Results from cnidarians, nematodes and mice also suggest an ancient neuronal role for the type 1 paracaspases.