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Front Immunol. 2018 May 24;9:1136. doi: 10.3389/fimmu.2018.01136. eCollection 2018.

Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions.

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Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research (IRC), Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Unit of Data Mining and Modeling for Biomedicine, VIB-UGent Center for Inflammation Research (IRC), Ghent, Belgium.
Unit of Molecular Cell Biology, VIB-UGent Center for Inflammation Research (IRC), Ghent, Belgium.
VIB Bio Imaging Core Gent, VIB-UGent Center for Inflammation Research (IRC), Ghent, Belgium.
Laboratory for Aging Physiology and Molecular Evolution, Biology Department, Ghent University, Ghent, Belgium.
Department of Biology, University of Texas Arlington, Arlington, TX, United States.
Department of Molecular Evolution and Development, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium.


The CARD-coiled coil (CC)/Bcl10/MALT1-like paracaspase (CBM) signaling complexes composed of a CARD-CC family member (CARD-9, -10, -11, or -14), Bcl10, and the type 1 paracaspase MALT1 (PCASP1) play a pivotal role in immunity, inflammation, and cancer. Targeting MALT1 proteolytic activity is of potential therapeutic interest. However, little is known about the evolutionary origin and the original functions of the CBM complex. Type 1 paracaspases originated before the last common ancestor of planulozoa (bilaterians and cnidarians). Notably in bilaterians, Ecdysozoa (e.g., nematodes and insects) lacks Bcl10, whereas other lineages have a Bcl10 homolog. A survey of invertebrate CARD-CC homologs revealed such homologs only in species with Bcl10, indicating an ancient common origin of the entire CBM complex. Furthermore, vertebrate-like Syk/Zap70 tyrosine kinase homologs with the ITAM-binding SH2 domain were only found in invertebrate organisms with CARD-CC/Bcl10, indicating that this pathway might be related to the original function of the CBM complex. Moreover, the type 1 paracaspase sequences from invertebrate organisms that have CARD-CC/Bcl10 are more similar to vertebrate paracaspases. Functional analysis of protein-protein interactions, NF-κB signaling, and CYLD cleavage for selected invertebrate type 1 paracaspase and Bcl10 homologs supports this scenario and indicates an ancient origin of the CARD-CC/Bcl10/paracaspase signaling complex. By contrast, many of the known MALT1-associated activities evolved fairly recently, indicating that unknown functions are at the basis of the protein conservation. As a proof-of-concept, we provide initial evidence for a CBM- and NF-κB-independent neuronal function of the Caenorhabditis elegans type 1 paracaspase malt-1. In conclusion, this study shows how evolutionary insights may point at alternative functions of MALT1.


Caenorhabditis elegans; NF-kappaB; Nematostella vectensis; coral bleaching; molecular evolution; protein–protein interaction; signal transduction; structure–function analysis

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