Related Experiment Video
Updated: Feb 9, 2026
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical
Jens Staal1,2, Yasmine Driege1,2, Mira Haegman1,2
1Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research (IRC), Ghent, Belgium.
Insights
The CARD-coiled coil (CC)/Bcl10/MALT1-like paracaspase (CBM) complex has ancient origins, predating bilaterians. Evolutionary analysis reveals conserved functions and suggests novel, non-canonical roles for MALT1 beyond immunity and inflammation.
Area of Science:
- Immunology
- Evolutionary Biology
- Molecular Biology
Background:
- The CARD-coiled coil (CC)/Bcl10/MALT1-like paracaspase (CBM) signaling complexes are crucial for immunity, inflammation, and cancer.
- MALT1 proteolytic activity is a therapeutic target, but its evolutionary origins and original functions remain unclear.
Purpose of the Study:
- To investigate the evolutionary history and ancestral functions of the CBM complex.
- To identify potential novel functions of MALT1 by examining its evolutionary conservation.
Main Methods:
- Comparative analysis of CARD-CC, Bcl10, and type 1 paracaspase homologs across diverse invertebrate and vertebrate species.
- Phylogenetic analysis to determine evolutionary relationships.
- Functional assays including protein-protein interactions, NF-κB signaling, and CYLD cleavage.
- Exploration of neuronal functions of MALT1 in Caenorhabditis elegans.
Main Results:
- Type 1 paracaspases originated before the last common ancestor of bilaterians and cnidarians.
- The CBM complex components (CARD-CC, Bcl10, paracaspase) likely co-evolved, with homologs found together in specific lineages.
- Vertebrate-like tyrosine kinase homologs (Syk/Zap70) were found in invertebrates possessing CARD-CC/Bcl10, suggesting an ancient signaling pathway.
- Functional analyses supported an ancient origin for the CBM complex, with many known MALT1 activities evolving more recently.
- Evidence for a CBM- and NF-κB-independent neuronal function of MALT1 in C. elegans was observed.
Conclusions:
- Evolutionary insights reveal an ancient origin for the CBM complex, with conserved functions predating many known roles.
- The conservation of CBM components suggests fundamental, potentially undiscovered, functions.
- MALT1 may possess novel, non-canonical functions, including roles outside of immune signaling, as suggested by its neuronal function in invertebrates.
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.
More Related Videos
Related Concept Videos
01:30Assembly of Signaling Complexes
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
01:21Testing a Claim about Mean: Unknown Population SD
Estimating a population mean requires the samples to be approximately normally distributed. The data should be collected from the randomly selected samples having no sampling bias. There is no specific requirement for sample size. But if the sample size is less than 30, and we don't know the population standard deviation, a different approach is used;...
01:57Protein Complexes with Interchangeable Parts
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
02:03What is Cell Signaling?
01:16Critical Region, Critical Values and Significance Level
In hypothesis testing, a sample statistic is converted to a test statistic using z, t, or chi-square distribution. A critical region is an area under the curve in probability distributions demarcated by the critical value. When the test statistic falls in this region, it suggests that the null hypothesis must be rejected. As this region contains all those values of the...
01:31Critical Values