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CARMA1, BCL-10 and MALT1 in lymphocyte development and activation

Key Points

  • CARMA1 is a member of the membrane-associated guanylate kinase (MAGUK) family of scaffold proteins that assemble signal-transduction complexes by binding to both transmembrane and intracellular signalling molecules at sites of cell–cell contact.

  • CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways.

  • Antigen-receptor-induced NF-κB activation mediated by CARMA1, BCL-10 and MALT1 is crucial for the activation and proliferation of mature B and T cells.

  • T-cell receptor-induced JNK activation through CARMA1, BCL-10 and MALT1 might have a role in T helper 1-cell differentiation.

  • In addition to impaired B-cell receptor signalling, mice deficient or mutated in Carma1, Bcl-10 or Malt1 have impaired B-cell proliferative responses to CD40 or lipopolysaccharide stimulation.

  • The mice also have a defect in B-cell development with reduced numbers of B1 cells and marginal-zone B cells.

  • Chromosomal translocations of the genes encoding BCL-10 and MALT1 are associated with the formation of B-cell lymphomas of the mucosa-associated lymphoid tissue.

  • Abnormal expression, activity and/or subcellular localization of BCL-10 or MALT1 might result from these chromosomal translocations and could lead to constitutive NF-κB activation, protection from apoptosis and uncontrolled cellular proliferation.

Abstract

CARMA1, BCL-10 and MALT1 are signalling proteins that have a key role in antigen-receptor-mediated lymphocyte activation through the nuclear factor-κB pathway. Recent genetic studies have revealed additional, previously unexpected roles for these proteins in the development of B and T cells, and in the CD40- and lipopolysaccharide-dependent activation of B cells. Here, I discuss recent advances in the understanding of the molecular and biological functions of these proteins.

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Figure 1: Antigen-receptor-induced NF-κB activation by CARMA1, BCL-10 and MALT1.
Figure 2: MAGUK structure and hypothetical model for MAGUK regulation.
Figure 3: Molecular structure and interactions of CARMA1, BCL-10 and MALT1.
Figure 4: Role of CARMA1, BCL-10 and MALT1 in lymphocyte activation and development.

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Acknowledgements

I acknowledge the financial support of the Swiss Cancer League (Oncosuisse) and the Swiss National Science Foundation and thank my colleagues H. Everett, F. Martinon and E. Meylan for critical comments on the manuscript.

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DATABASES

LocusLink

BAFFR

BCL-10

BTK

CARMA1

CD40

CD95

cIAP2

c-Rel

IFN-γ

IKK-α

IKK-β

JNK2

Lat

Lck

MALT1

NF-κB1

NF-κB2

PKC-β

PKC-θ

PLC-γ2

RelA

RelB

Slp76

TRAF2

TRAF6

VAV1

Zap70

ZO-1

Glossary

LIPID RAFTS

Microdomains in the plasma membrane that are enriched in cholesterol and sphingolipids and that allow for the local concentration of specific signalling components while excluding others.

CD3 CAPPING EXPERIMENTS

Incubation of T cells with a CD3-specific antibody and a crosslinking secondary antibody at 37°C to induce the capping (local aggregation on the cell surface) of CD3–T-cell receptor complexes and associated signalling molecules, thereby mimicking some aspects of immunological synapse formation.

METACASPASES

A family of caspase-like proteins of unknown function found in plants, fungi and protozoa.

UNMODULATED MICE

A recessive mouse mutant that has a point mutation in the coiled-coil motif of Carma1, which causes impaired (unmodulated) downregulation of cell-surface IgM expression by mature recirculating B cells.

MARGINAL-ZONE (MZ) B CELLS

Long-lived B cells that are thought to function as a first line of defence against blood-born particulate antigens in the MZ of the spleen germinal centres. MZ B cells are highly sensitive to lipopolysaccharide- and CD40-stimulation, after which they undergo rapid proliferation and differentiation into plasma cells secreting high levels of IgM.

TRANSITIONAL TYPE B CELLS

B-cell precursor cells found in the spleen that can give rise to marginal-zone B cells or to mature follicular B cells.

B1 CELLS

Long-lived, self-renewing B cells found in the peritoneal and pleural cavities, in which they are thought to provide a T-cell-independent humoral response against polyvalent antigens.

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Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat Rev Immunol 4, 348–359 (2004). https://doi.org/10.1038/nri1352

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