GO:0032449 CBM complex: Components, Assembly and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0032449 (CBM complex) describes a cytoplasmic signalosome composed of a CARD-domain scaffold (CARD9, CARD10 or CARD11), BCL10 and MALT1 that couples antigen receptor and pattern-recognition receptor signaling to NF-kappaB activation.
• The CBM complex is best known for transducing T-cell receptor and B-cell receptor signals, but it also operates downstream of C-type lectin receptors in myeloid cells through CARD9-containing complexes.
• MALT1 is the enzymatic subunit of the complex; its paracaspase activity and scaffolding function are both required for full NF-kappaB and MAPK pathway activation.
• Germline mutations in CARD11, BCL10 and MALT1 cause a spectrum of inborn errors of immunity collectively called CBM-opathies, ranging from severe combined immunodeficiency to B-cell lymphocytosis and atopic disease.
• The CBM complex is a therapeutic target in oncology: targeting it can destabilize regulatory T cells and sensitize tumors to immune checkpoint blockade.
• CRISPR-based knockout, point-mutation, knock-in and overexpression models are widely used to dissect CBM complex assembly, signaling and disease-associated variants.
Description
The CBM complex (GO:0032449) is a cytoplasmic protein assembly that serves as a central signaling hub for NF-kappaB activation downstream of antigen receptors and innate immune receptors. Its name derives from its three core components: a CARD-domain-containing scaffold protein (CARD9, CARD10 or CARD11), BCL10, and MALT1. The complex is conserved in adaptive and innate immune cells and is essential for lymphocyte activation, cytokine production and immune homeostasis. Because the CBM complex sits at the intersection of immune receptor signaling and NF-kappaB-driven gene expression, it has become a focal point for researchers studying immunodeficiency, autoimmunity, allergy and cancer. At the molecular level, the CBM complex functions as a nucleating platform: receptor-proximal kinases phosphorylate the CARD scaffold, which then recruits BCL10 and MALT1 to form a high-molecular-weight signalosome. This assembly enables MALT1 to act both as a scaffold and as a paracaspase that cleaves negative regulators of NF-kappaB signaling. The complex also interfaces with MAPK pathways and with ubiquitin-modifying enzymes such as LUBAC, broadening its regulatory reach. For researchers, GO:0032449 provides a precise annotation for experiments that interrogate immune signaling, lymphocyte biology and NF-kappaB-dependent transcription. Understanding the composition, assembly and regulation of the CBM complex is therefore critical for interpreting genetic variants, designing targeted therapies and building accurate disease models.
CBM complex At A Glance
| GO ID | GO:0032449 |
|---|---|
| GO term | CBM complex |
| Ontology | cellular_component |
| Synonym | CARMA1-BCL10-Malt1 complex |
| Definition | A protein complex comprising Bcl10, MALT1 and a CARD domain-containing protein (CARD9, CARD10 or CARD11); plays a role in signal transduction during NF-kappaB activation. |
| Major function | Signal transduction during NF-kappaB activation downstream of antigen receptors and pattern-recognition receptors. |
| Core subunits | CARD9, CARD10 or CARD11; BCL10; MALT1. |
| Subcellular location | Cytoplasm; recruited to receptor-proximal signaling platforms. |
| Disease relevance | Inborn errors of immunity (CBM-opathies), allergic inflammation, autoimmunity and lymphoid malignancies. |
What Is GO:0032449?
The CBM complex is a protein complex that contains BCL10, MALT1 and one CARD-domain-containing protein, which can be CARD9, CARD10 or CARD11. It participates in intracellular signal transduction leading to activation of the NF-kappaB transcription factor. The complex is also known as the CARMA1-BCL10-MALT1 complex when CARD11 (CARMA1) is the scaffold subunit.
Why Is CBM complex Important in Cell Biology?
The CBM complex is important because it converts receptor-proximal signals from antigen receptors and innate immune receptors into NF-kappaB-dependent transcriptional programs that control lymphocyte activation, survival and effector function. Disruption of CBM complex components causes severe human immunodeficiencies, while hyperactive CBM signaling contributes to allergic inflammation and lymphoid malignancies. In cancer immunology, targeting the CBM complex can selectively impair regulatory T cells and enhance antitumor immunity. Consequently, GO:0032449 is a key annotation for studies of immune signaling, disease genetics and therapeutic targeting.
• Essential for T-cell receptor and B-cell receptor signaling to NF-kappaB.
• Required for innate immune signaling downstream of C-type lectin receptors via CARD9-containing complexes.
• Germline mutations cause CBM-opathies, a spectrum of primary immunodeficiencies.
• Hyperactivation is linked to allergic inflammation and atopic disease.
• Contributes to the tumor microenvironment by modulating regulatory T cells.
• MALT1 paracaspase activity is a druggable node in B-cell lymphomas.
• Interfaces with MAPK and ubiquitin signaling pathways.
• Serves as a model system for studying signalosome assembly and NF-kappaB dynamics.
Structure and Composition of CBM complex
CARD scaffold proteins (CARD9, CARD10, CARD11)
In simple terms: The CARD protein is the base that starts the assembly.
The CBM complex is nucleated by a CARD-domain-containing scaffold: CARD11 (also called CARMA1) in lymphocytes, CARD9 in myeloid cells, or CARD10 in other contexts. These scaffolds are recruited to receptor-proximal signaling platforms through their N-terminal domains and are phosphorylated by kinases such as PKC isoforms, which relieves autoinhibition and permits BCL10 binding. CARD9 forms an alternative CBM complex in Richter syndrome, highlighting context-dependent scaffold usage.
BCL10 as the bridging subunit
In simple terms: BCL10 links the CARD protein to MALT1.
BCL10 contains an N-terminal CARD domain that binds the CARD domain of the scaffold protein and a C-terminal region that recruits MALT1. BCL10 is constitutively expressed in lymphocytes and is essential for CBM complex integrity; its deficiency abolishes NF-kappaB activation downstream of antigen receptors. BCL10 also forms filaments that template higher-order assembly of the signalosome.
MALT1 as scaffold and paracaspase
In simple terms: MALT1 is the enzyme and glue of the complex.
MALT1 binds BCL10 and serves both as a scaffold that stabilizes the complex and as a paracaspase that cleaves substrates such as A20 and CYLD to sustain NF-kappaB signaling. Its catalytic activity is regulated by monoubiquitination and by interactions with LUBAC downstream of TRAF6 in T cells. MALT1 inhibitors are being explored as therapeutic agents in B-cell malignancies.
Assembly and higher-order oligomerization
In simple terms: The pieces come together into a large signaling machine.
CBM complex assembly proceeds through receptor-induced phosphorylation of the CARD scaffold, recruitment of BCL10, and subsequent binding of MALT1, forming high-molecular-weight oligomers. This oligomerization is required for efficient NF-kappaB activation and for crosstalk with MAPK pathways. The complex is transient and tightly regulated by ubiquitination and phosphorylation events.
Interacting partners and regulatory modules
In simple terms: Other proteins attach to the complex to tune its output.
The CBM complex interacts with ubiquitin ligases such as LUBAC and TRAF6, which modify its subunits and modulate downstream signaling. It also crosstalks with MAPK/P27 signaling in regulatory T cells, influencing the tumor microenvironment. These interactions expand the functional repertoire of the complex beyond canonical NF-kappaB activation.
Key Genes Involved in GO:0032449 CBM complex
The following genes encode the core subunits and key regulators of the CBM complex.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CARD11 | Lymphoid CARD scaffold that nucleates the CBM complex | Mutations cause immunodeficiency and lymphoma; target for signaling studies |
| CARD9 | Myeloid CARD scaffold forming an alternative CBM complex | Involved in antifungal immunity and Richter syndrome |
| CARD10 | Non-lymphoid CARD scaffold (CARMA3) in CBM-like complexes | Context-dependent NF-kappaB activation |
| BCL10 | Bridging subunit linking CARD scaffold to MALT1 | Essential for CBM integrity; mutations cause immunodeficiency |
| MALT1 | Paracaspase and scaffold subunit | Drug target in B-cell lymphoma; regulates NF-kappaB |
| TRAF6 | E3 ubiquitin ligase upstream of CBM complex | Modulates CBM function via LUBAC |
| LUBAC | Linear ubiquitin chain assembly complex | Regulates CBM complex downstream of TRAF6 |
| PKC-beta | Kinase that phosphorylates CARD11 | Required for CBM assembly in lymphocytes |
| PKC-theta | Kinase that phosphorylates CARD11 in T cells | Required for CBM assembly in T cells |
| A20 (TNFAIP3) | NF-kappaB negative regulator cleaved by MALT1 | MALT1 substrate; feedback regulation |
| CYLD | Deubiquitinase cleaved by MALT1 | MALT1 substrate; feedback regulation |
| NFKB1 | NF-kappaB transcription factor subunit | Downstream effector of CBM signaling |
| REL | NF-kappaB transcription factor subunit | Downstream effector of CBM signaling |
| FOXP3 | Regulatory T-cell transcription factor | CBM complex modulates Treg function in tumors |
| IL2 | T-cell growth factor | Readout of CBM-dependent NF-kappaB activation |
| CD28 | Costimulatory receptor | Cooperates with TCR to activate CBM complex |
How Is CBM complex Regulated?
CBM complex activity is regulated at multiple levels. Receptor-proximal kinases such as PKC isoforms phosphorylate the CARD scaffold to relieve autoinhibition and permit BCL10 binding. Ubiquitination by TRAF6 and LUBAC modulates complex stability and downstream signaling, with LUBAC acting downstream of TRAF6 in T cells. MALT1 paracaspase activity is controlled by monoubiquitination and by its own cleavage of negative regulators such as A20 and CYLD, creating feedback loops. In regulatory T cells, crosstalk between CBM/NF-kappaB and MAPK/P27 pathways shapes the tumor microenvironment. These layers of regulation ensure that CBM signaling is transient and context-specific.
CBM complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CARD11 | CBM-opathy; B-cell lymphocytosis; atopic disease | Knock-in of patient variants in T-cell lines |
| BCL10 | Immunodeficiency with NF-kappaB defect | Knockout in Jurkat T cells |
| MALT1 | Immunodeficiency; B-cell lymphoma | Paracaspase-dead knock-in in lymphoma lines |
| CARD9 | Richter syndrome; antifungal immunity | Knockout in myeloid cells |
| FOXP3 | Tumor microenvironment; Treg function | CBM-targeted knockout in Tregs |
CBM-opathies: inborn errors of immunity
Germline mutations in CARD11, BCL10 or MALT1 cause a spectrum of primary immunodeficiencies known as CBM-opathies, which can present as severe combined immunodeficiency, combined immunodeficiency with immune dysregulation, or B-cell lymphocytosis with atopy. These disorders highlight the non-redundant role of the CBM complex in human immunity.
Allergic inflammation and atopic disease
The CBM complex contributes to allergic inflammation by transducing signals downstream of Fc-epsilon receptors and C-type lectin receptors. Dysregulated CBM signaling is associated with atopic dermatitis, asthma and food allergy, making it a potential target for anti-allergic therapy.
Lymphoid malignancies and cancer immunotherapy
CARD9 forms an alternative CBM complex in Richter syndrome, and MALT1 is constitutively active in activated B-cell-like diffuse large B-cell lymphoma. Targeting the CBM complex can destabilize regulatory T cells and prime tumors for immune checkpoint therapy, as shown in preclinical models.
From CBM complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of CARD11 abolish NF-kappaB activation? | CARD11 knockout in Jurkat or primary T cells |
| Does a patient variant impair CBM assembly? | Point-mutation knock-in of CARD11 variant |
| Does MALT1 catalytic activity require monoubiquitination? | MALT1 point-mutation knock-in |
| Can CBM targeting enhance checkpoint therapy? | CBM complex knockout in Tregs in mouse tumor models |
| Does CARD9 form an alternative CBM complex? | CARD9 overexpression in B-cell lines |
| How does LUBAC regulate CBM function? | LUBAC knockout or tagged knock-in in T cells |
How to Study the CBM complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Co-immunoprecipitation | Protein-protein interactions | Defining CBM complex composition |
| Mass spectrometry | Proteomic composition | Identifying CBM interactors |
| NF-kappaB luciferase reporter | Transcriptional activity | Testing CBM mutations |
| MALT1 activity assay | Paracaspase activity | Evaluating inhibitors |
| CRISPR knockout screen | Gene essentiality | Finding CBM regulators |
| Phospho-flow cytometry | Phosphorylation of signaling proteins | Measuring CBM activation |
| Proximity ligation assay | In situ protein interactions | Visualizing CBM assembly |
Co-immunoprecipitation and mass spectrometry
Co-immunoprecipitation followed by mass spectrometry is used to define the composition of the CBM complex and its interacting partners under different stimulation conditions. These methods can identify context-specific scaffold usage, such as CARD9 versus CARD11.
NF-kappaB reporter assays
Luciferase-based NF-kappaB reporter assays are standard for measuring CBM complex activity downstream of receptor stimulation. They are used to test the impact of mutations in CARD11, BCL10 or MALT1 on signaling output.
Protease activity assays for MALT1
MALT1 paracaspase activity can be measured using fluorogenic peptide substrates or by monitoring cleavage of endogenous substrates such as A20 and CYLD. These assays are used to evaluate MALT1 inhibitors and to study feedback regulation.
CRISPR screens and functional genomics
Genome-wide CRISPR knockout screens have been used to identify regulators of CBM complex signaling and to uncover synthetic lethal interactions in lymphoma cells. These screens provide unbiased insights into pathway architecture and therapeutic vulnerabilities.
How CRISPR Can Be Used to Study GO:0032449 CBM complex
Knockout
CRISPR knockout of CARD11, BCL10 or MALT1 is used to abolish CBM complex function and to test its requirement for NF-kappaB activation, cytokine production and lymphocyte proliferation. Knockout models are also used to validate drug targets and to study immune cell development.
Point Mutation
Point-mutation knock-in models are used to dissect the function of specific residues, such as those required for MALT1 catalytic activity or for CARD11 phosphorylation. These models help distinguish scaffolding from enzymatic functions and can recapitulate patient variants.
Knock-in
Knock-in of tagged or fluorescently labeled CBM components enables live-cell imaging and proteomic analysis of complex assembly. Knock-in of disease-associated alleles in cell lines or mice provides models for CBM-opathies and lymphoma.
Overexpression
Overexpression of CARD9, CARD10 or CARD11 with BCL10 and MALT1 is used to reconstitute CBM complex signaling in heterologous cells and to study gain-of-function variants. Overexpression systems are also useful for structural and biochemical studies of the complex.
How EDITGENE Supports CBM complex Research
Researchers studying CBM complex-related genes often need to determine whether a candidate gene is causally involved in NF-kappaB signaling, immune cell function or disease pathogenesis. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models for such studies.
Contact EDITGENE today to design your custom CRISPR model for CBM complex research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CARD11 Knockout HEK293 Cell Line | EDJ-KQ138 | Human | 84433 | Details Get a Quote |
| CARD10 Knockout HEK293 Cell Line | EDJ-KQ545 | Human | 29775 | Details Get a Quote |
| CARD14 Knockout HEK293 Cell Line | EDJ-KQ546 | Human | 79092 | Details Get a Quote |
| MALT1 Knockout HEK293 Cell Line | EDJ-KQ576 | Human | 10892 | Details Get a Quote |
| CARD9 Knockout HEK293 Cell Line | EDJ-KQ12725 | Human | 64170 | Details Get a Quote |
| CARD10 Knockout A-549 Cell Line | EDJ-KQ18919 | Human | 29775 | Details Get a Quote |
| CARD10 Knockout HCT 116 Cell Line | EDJ-KQ18920 | Human | 29775 | Details Get a Quote |
| CARD10 Knockout HeLa Cell Line | EDJ-KQ18921 | Human | 29775 | Details Get a Quote |
| CARD11 Knockout HeLa Cell Line | EDJ-KQ18923 | Human | 84433 | Details Get a Quote |
| MALT1 Knockout A-549 Cell Line | EDJ-KQ18972 | Human | 10892 | Details Get a Quote |
| MALT1 Knockout HCT 116 Cell Line | EDJ-KQ18973 | Human | 10892 | Details Get a Quote |
| MALT1 Knockout HeLa Cell Line | EDJ-KQ18974 | Human | 10892 | Details Get a Quote |
| BCL10 Knockout HEK293 Cell Line | EDJ-KQ50830 | Human | 8915 | Details Get a Quote |
| BCL10 Knockout HeLa Cell Line | EDJ-KQ55035 | Human | 8915 | Details Get a Quote |
| CARD9 Knockout HeLa Cell Line | EDJ-KQ57038 | Human | 64170 | Details Get a Quote |
Frequently Asked Questions About CBM complex
What is the CBM complex?
The CBM complex is a protein complex composed of a CARD-domain scaffold (CARD9, CARD10 or CARD11), BCL10 and MALT1 that transduces signals to activate NF-kappaB.
What genes are involved in the CBM complex?
The core genes are CARD9, CARD10, CARD11, BCL10 and MALT1, with regulators such as TRAF6, LUBAC, PKC isoforms, A20 and CYLD.
What is GO:0032449?
GO:0032449 is the Gene Ontology identifier for the CBM complex, a cellular component involved in NF-kappaB signal transduction.
What diseases are associated with CBM complex mutations?
Mutations cause CBM-opathies, a spectrum of inborn errors of immunity, and dysregulation is linked to allergic inflammation and lymphoid malignancies.
How is the CBM complex regulated?
It is regulated by phosphorylation of the CARD scaffold, ubiquitination by TRAF6 and LUBAC, and MALT1 paracaspase activity.
What is the role of MALT1 in the CBM complex?
MALT1 is both a scaffold and a paracaspase that cleaves negative regulators of NF-kappaB, sustaining signaling.
Can the CBM complex be targeted for cancer therapy?
Yes, targeting the CBM complex can destabilize regulatory T cells and enhance immune checkpoint therapy in preclinical models.
What cell models are used to study the CBM complex?
Common models include CRISPR knockout, point-mutation knock-in, tagged knock-in and overexpression cell lines in T cells, B cells and myeloid cells.
What is the difference between CARD9 and CARD11 in the CBM complex?
CARD11 is the primary scaffold in lymphocytes, while CARD9 forms an alternative CBM complex in myeloid cells and in Richter syndrome.
How can I study CBM complex assembly?
Co-immunoprecipitation, mass spectrometry, proximity ligation assays and live-cell imaging of tagged subunits are standard approaches.
Conclusion
The CBM complex (GO:0032449) is a central signalosome that links immune receptor activation to NF-kappaB-dependent transcription. Its core components, CARD9/CARD10/CARD11, BCL10 and MALT1, are essential for lymphocyte and innate immune function, and their dysregulation causes immunodeficiencies, allergic inflammation and lymphoid malignancies. Continued research using CRISPR-engineered models will clarify the mechanistic details of CBM assembly and identify new therapeutic opportunities.
References
- 1. DeVore SB et al.. 2022. The role of the CBM complex in allergic inflammation and disease.. J Allergy Clin Immunol 150(5):1011-1030 PMID: 35981904
- 2. Di Pilato M et al.. 2019. Targeting the CBM complex causes T(reg) cells to prime tumours for immune checkpoint therapy.. Nature 570(7759):112-116 PMID: 31092922
- 3. Graß C et al.. 2025. LUBAC modulates CBM complex functions downstream of TRAF6 in T cells.. Nat Commun 16(1):9899 PMID: 41213928
- 4. Qi T et al.. 2022. Crosstalk between the CBM complex/NF-κB and MAPK/P27 signaling pathways of regulatory T cells contributes to the tumor microenvironment.. Front Cell Dev Biol 10:911811 PMID: 35927985
- 5. Turvey SE et al.. 2014. The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.. J Allergy Clin Immunol 134(2):276-84 PMID: 25087226
- 6. Schaefer BC. 2020. The CBM complex: A growing multiplicity of cellular functions, regulatory mechanisms and connections to human disease.. Cell Immunol 356:104189 PMID: 32771677
- 7. Maier J et al.. 2022. CARD9 Forms an Alternative CBM Complex in Richter Syndrome.. Cancers (Basel) 14(3) PMID: 35158799
- 8. Lu HY et al.. 2018. The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex.. Front Immunol 9:2078 PMID: 30283440
