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  • Review Article
  • Published:

The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes

Nature Reviews Immunology volume 6, pages 799–812 (2006)Cite this article

Key Points

  • Recent experimental evidence resolves two important gaps in our understanding of the molecular mechanisms by which antigen receptors signal to activate nuclear factor-κB (NF-κB). This new information includes: first, how protein kinase C (PKC) isoforms directly activate the CARMA1 (caspase-recruitment domain (CARD)–membrane-associated guanylate kinase (MAGUK) protein 1) signalosome; and second, how specific signalling molecules that also promote NF-κB activation downstream of innate immune receptors participate in this pathway following the recruitment of MALT1 (mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1).

  • Antigen-receptor stimulation initiates a proximal tyrosine-phosphorylation cascade that promotes activation of phospholipase C-γ isoforms, leading to the production of second messengers that are essential for PKC activation. Activated PKCβ (in B cells) and PKCθ (in T cells) subsequently phosphorylate key serine residues in the PKC-regulated domain (PRD) of CARMA1.

  • In unstimulated cells, CARMA1 assumes a closed conformation through intramolecular interactions. PKC-mediated phosphorylation of the PRD of CARMA1 triggers a conformational change that exposes downstream CARMA1 protein-binding domains required for signalosome assembly, including: the CARD required for B-cell lymphoma 10 (BCL-10) binding, the coiled-coil (CC) domain for CARMA1 oligomerization, and the GUK domain, which is predicted to mediate higher-order multimerization of oligomerized CARMA1 complexes.

  • Activated CARMA1 initiates an oligomerization cascade of BCL-10 and MALT1, which is followed by the recruitment of trimerized TRAF2 (tumour-necrosis factor receptor (TNFR)-associated factor 2) or TRAF6. On the basis of studies of innate immune-receptor signalling, TRAF2 or TRAF6 oligomerization stimulates TRAF-mediated K63-linked polyubiquitylation of target proteins. These K63-linked polyubiquitylated targets then function as scaffolds that recruit ubiquitin-binding proteins associated with TAK1 (transforming-growth-factor-β-activated kinase 1) and IKK (inhibitor of nuclear factor-κB (IκB) kinase) complexes into the CARMA1 signalosome.

  • The specific and non-redundant role for CARMA1 in antigen-receptor-mediated activation of NF-κB makes this protein an appealing target for pharmacological regulation in a range of specific immune disorders, as well in human B-cell lymphomas characterized by dysregulated NF-κB activation.

Abstract

The recognition of antigen by B- or T-cell receptors initiates an intracellular signalling cascade that results in the nuclear translocation and activation of the transcription factor nuclear factor-κB (NF-κB). NF-κB is an important regulator of lymphocyte development and function, and its dysregulation is associated with many immune disorders. Defining the mechanisms that transmit signals from the antigen receptor to NF-κB is therefore an important goal for immunologists. In this Review, we merge information gleaned from research of the innate immune system with what we know about antigen-receptor signals in the adaptive immune system, to propose a cohesive model of how antigen receptors activate NF-κB.

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Figure 1: Signalling pathways of innate and adaptive immune receptors.
Figure 2: Model for protein-kinase-C-mediated CARMA1 activation.
Figure 3: Model of the CARMA1-signalosome oligomerization cascade and IKK activation.

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Acknowledgements

We thank A. Hui for assistance with the mauscript. D.J.R. is the recipient of a McDonnell Scholar Award and a Leukemia and Lymphoma Society Scholar Award. This work was supported, in part, by NIH grants and by the American Cancer Society.

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  1. Department of Immunology, Childrens Hospital & Regional Medical Centre, 307 Westlake Avenue North, Suite 300, Seattle, 98109, Washington, USA

    David J. Rawlings, Karen Sommer & Miguel E. Moreno-García

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  1. David J. Rawlings
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Glossary

Non-canonical pathway of NF-κB signalling

An alternative pathway by which the nuclear factor-κB (NF-κB) transcription factor can be released from the cytoplasm into the nucleus. Unlike NF-κB1 (p105/p50) in the classical (canonical) NF-κB pathway, NF-κB2 (p100/p52) is not pre-cleaved. An IκB (inhibitor of NF-κB) domain in the carboxyl terminus of p100 tethers it in the cytosol. Activation of specific receptors (for example, CD40) induces p100 phosphorylation by IκB kinase-α, which targets p100 for proteasomal degradation. Only the IκB domain is degraded by the proteasome, leaving the portion of p100 with transcription-factor activity (p52) intact and able to translocate to the nucleus.

Ubiquitylation

The attachment of the small protein ubiquitin to lysine residues present in other proteins. Subsequent ubiquitylation events can extend from the initial ubiquitin at one of its seven lysine residues (K6, K11, K27, K29, K33, K48 or K63), forming a polyubiquitin chain.

Lipid rafts

Semi-rigid lipid microdomains of the cell membrane that are enriched for sphingolipids and cholesterol. Certain signalling molecules selectively localize to lipid rafts, either constitutively or inducibly in response to a stimulus.

E3 ubiquitin ligase

Protein ubiquitylation occurs in three enzymatic steps, requiring a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3), which catalyses the ligation of an isopeptide bond between the carboxy-terminal domain of ubiquitin and an amino group belonging to a lysine residue of the target protein.

K63-linked ubiquitylation

The addition of ubiquitin to lysine side chains of target proteins using the lysine at position 63 (K63) of ubiquitin. Unlike K48-linked ubiquitin chains, which are the main signal for targeting substrates for proteasomal degradation, K63-linked ubiquitin modification regulates protein function, targets certain proteins for endocytosis, and interacts with proteins with specific ubiquitin-binding domains.

Cre–loxP system

A site-specific recombination system. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Expression of Cre recombinase leads to excision of the intervening sequence. Depending on the type of promoter, Cre can be expressed at specific times during development or in specific sets of cells.

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Rawlings, D., Sommer, K. & Moreno-García, M. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6, 799–812 (2006). https://doi.org/10.1038/nri1944

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