Abstract
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.
Highlights
The paracaspase MALT1 (PCASP1) was originally identified in humans as an oncogenic fusion with IAP2 in low-grade antibioticresistant MALT lymphomas [1]
In order to unravel the evolutionary history of the CBM complex, the sequences of CARD–coiled coil (CC), Bcl10, and other CBM complex-associated proteins were investigated through mining of several sequence databases and through phylogenetic analyses
The presence of invertebrate Syk/ Zap70 homologs correlates with the presence of Bcl10 and CARD–CC (Figure 1; Figures S1B and S2 in Supplementary Material)
Summary
The paracaspase MALT1 (PCASP1) was originally identified in humans as an oncogenic fusion with IAP2 in low-grade antibioticresistant MALT lymphomas [1]. CARD-11 ( known as CARMA1) belongs to a distinct phylogenetic group of CARD domain proteins, which is characterized by a CARD and a coiled-coil (CC) domain, and this group of proteins will be referred to as CARD–CC proteins Further studies made it clear that MALT1 plays a role in several different CARD–CC/Bcl10/MALT1 signaling complexes, which are composed of specific CARD–CC family proteins [CARD-9 [6], CARD-11 [4], CARD-14 ( known as CARMA2) [7,8,9], and CARD-10 ( known as CARMA3) [10]] and which are formed upon the stimulation of distinct receptors in several immune and non-immune cells. Finding those alternative functions of MALT1 could be important in the context of future MALT1 inhibitor-based therapies [32] and could help identify yet undiscovered issues that might affect patients deficient in MALT1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
