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The multifaceted roles of TRAFs in the regulation of B-cell function

Nature Reviews Immunology volume 4, pages 775–786 (2004)Cite this article

Key Points

  • TRAFs (tumour-necrosis factor receptor (TNFR)-associated factors) have multiple roles in B-cell biology. These include involvement in cellular activation, differentiation and the apoptotic signals delivered by receptors of both the TNFR family and the Toll-like receptor family.

  • The main structural features of TRAFs are similar. Various domains of TRAFs regulate their receptor binding, the multimerization of TRAFs and their interaction with cellular signalling cascades.

  • Receptors recruit TRAFs to membrane signalling complexes. Before receptor engagement, TRAFs are mainly present in the cytoplasm. Ligand binding to receptors induces the rapid recruitment of TRAFs to lipid and signal-protein-enriched membrane rafts, which is followed, in some cases, by their degradation.

  • TRAFs mediate both unique and similar, overlapping functions in B cells. Although each member of the TRAF family expressed by B cells makes unique contributions to B-cell biology, it has recently been shown that TRAFs can also substitute for one another in certain signalling pathways.

  • Interactions between TRAFs regulate TRAF functions. In addition to forming homotrimers, TRAFs can form heteromultimers, and these combinations add to the number and variety of biological functions TRAFs can mediate.

  • Specific TRAF roles vary widely between receptors. TRAFs can have sharply divergent roles, mediating either activating or inhibitory signals, depending on which receptors they associate with and the composition of the signalling complex.

Abstract

Tumour-necrosis factor receptor (TNFR)-associated factors (TRAFs) are cytoplasmic adaptor proteins that are important in lymphocyte activation and apoptosis. Many studies of TRAFs have used models of exogenous overexpression by non-lymphoid cells. However, the actions of TRAFs present at normal levels in lymphoid cells often differ considerably from those that have been established in non-lymphocyte overexpression models. As I discuss here, information obtained from studying these molecules in physiological settings in B cells reveals that they have several roles, which are both unique and overlapping. These include activation of kinases and transcription factors, and interactions with other signalling proteins, culminating in the induction or inhibition of biological functions.

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Figure 1: Main structural features of TRAFs.
Figure 2: Formation of a CD40–TRAF-signalling complex in lipid rafts.
Figure 3: TRAFs can mediate both unique and overlapping functions in CD40-mediated B-cell activation.
Figure 4: The functional roles of TRAFs are receptor specific.
Figure 5: CD40–TRAF-activated signalling pathways that lead to gene regulation.

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Acknowledgements

The author is grateful to members of her laboratory and B. Hostager for valuable discussions.

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Authors and Affiliations

  1. Departments of Microbiology and Internal Medicine, The University of Iowa, Veterans' Affairs Medical Center, Iowa City, 52242, Iowa, USA

    Gail A. Bishop

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DATABASES

Entrez Gene

BAFF

BAFFR

BCMA

CD20

CD27

CD30

CD40

CD95

CD120a

CD120b

CD154

RANK

TACI

TNF

TRAF1

TRAF2

TRAF3

TRAF6

TRAIL

FURTHER INFORMATION

Gail Bishop's laboratory

Glossary

TOLL-LIKE RECEPTOR (TLR) FAMILY

A family of receptors that recognize conserved products unique to microorganisms (such as lipopolysaccharide), which are known as pathogen-associated molecular patterns (PAMPs). TLR-mediated events signal to the host that a microbial pathogen is present.

RING DOMAIN

(Really interesting new gene domain). A cysteine-rich motif found in several hundred proteins from diverse eukaryotes.

AGONISTIC

An artificial receptor stimulus that mimics the effects of natural ligand binding.

LIPID RAFTS

Areas of the plasma membrane that are rich in cholesterol, glycosphingolipids and glycosylphosphatidylinositol-anchored proteins. They are also known as glycolipid-enriched membrane domains (GEMs) and detergent-insoluble glycolipid-enriched membranes (DIGs).

UBIQUITYLATION

The addition of one or more ubiquitin residues to a protein.

E3 UBIQUITIN LIGASE

The enzyme that is required to attach the molecular tag ubiquitin to proteins that are destined for degradation by the proteasomal complex.

DOMINANT-NEGATIVE PROTEINS

Defective proteins that retain the ability to interact but lack enzymatic activity, so they distort or compete with normal proteins.

HOMOLOGOUS RECOMBINATION

Genetic recombination that occurs between regions of DNA with long stretches of homology. This occurs with a low frequency in somatic cells and at a much higher frequency in germ cells.

ALYMPHOPLASIA

(aly). A mouse phenotype that is characterized by the absence of lymph nodes and Peyer's patches. It is caused by a spontaneous mutation in the gene that encodes nuclear-factor-κB-inducing kinase (NIK).

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Bishop, G. The multifaceted roles of TRAFs in the regulation of B-cell function. Nat Rev Immunol 4, 775–786 (2004). https://doi.org/10.1038/nri1462

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