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  • Review Article
  • Published:

Expanding TRAF function: TRAF3 as a tri-faced immune regulator

Nature Reviews Immunology volume 11, pages 457–468 (2011)Cite this article

Subjects

Key Points

  • TNFR-associated factors (TRAFs) constitute a family of seven cytoplasmic proteins that control signal transduction from different receptor families, including the tumour necrosis factor receptors (TNFRs), Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). Therefore, TRAFs regulate various downstream signalling pathways, such as the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) pathways, and control a plethora of biological functions, both in immune and non-immune cell types.

  • TRAFs share a similar domain organization. Receptors and other upstream proteins engage TRAFs typically via their carboxy-terminal TRAF domain, whereas the amino-terminal region promotes the synthesis of non-degradative K63-linked polyubiquitin chains, which are required for downstream signal transduction.

  • The function of TRAF3 remained unclear until recent studies demonstrated that it can perform at least three different molecular functions, depending on the engaging receptor and its interplay with other proteins, such as TRAF2, the E3 ubiquitin ligases cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2 and the protein kinase NF-κB-inducing kinase (NIK; also known as MAP3K14).

  • In TLR and RLR signalling pathways, TRAF3 is recruited into signalling complexes following pathogen encounter and acts as a ubiquitin ligase, promoting the synthesis of K63-linked polyubiquitin chains that control the activation of the type I interferon response. A patient with a destabilizing mutation in TRAF3 has been described who suffered from paediatric herpes simplex encephalitis, supporting the idea that TRAF3 functions in antiviral immune defence in humans.

  • Following the activation of certain TLRs and TNFRs (such as TLR4 and CD40), TRAF3 acts as a negative regulator, and its degradation is required for MAPK activation and the regulation of immune effector functions (for example, pro-inflammatory cytokine production). Receptor activation and the formation of a membrane-associated signalling complex leads to cIAP-mediated degradation of TRAF3, thereby liberating multiprotein complexes that contain MEK kinase 1 (MEKK1; also known as MAP3K1) and TGFβ-activated kinase 1 (TAK1; also known as MAP3K7) into the cytoplasm, where they activate downstream MAPK pathways.

  • Together with TRAF2 and cIAPs (and possibly other proteins), TRAF3 serves as a constitutive negative regulator of the alternative NF-κB pathway, which controls B cell survival and lymphoid organ development. Activation of a subset of TNFRs (including CD40, the BAFF receptor and the lymphotoxin-β receptor) results in cIAP-mediated TRAF3 degradation and the liberation of NIK, and this in turn leads to IκB kinase-α (IKKα)-mediated NF-κB activation. Mutations in several negative regulatory components in this pathway, including TRAF3, have been identified in cancer cells from patients with multiple myeloma, resulting in increased NF-κB activity and cancer cell survival.

Abstract

Tumour necrosis factor receptor (TNFR)-associated factor (TRAF) proteins are essential components of signalling pathways activated by TNFR or Toll-like receptor (TLR) family members. Acting alone or in combination, the seven known TRAFs control many biological processes, including cytokine production and cell survival. The function of one TRAF in particular, TRAF3, remained elusive for many years. Recent work has revealed that TRAF3 is a highly versatile regulator that positively controls type I interferon production, but negatively regulates mitogen-activated protein kinase activation and alternative nuclear factor-κB signalling. In this Review, we discuss our current understanding of the role of TRAF3 in TNFR and TLR signalling pathways, and its role in disease.

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Figure 1: Domain organization of mammalian TRAF proteins.
Figure 2: Adaptors and signalling complexes used by members of the TLR and IL-1R families.
Figure 3: The two NF-κB activation pathways.
Figure 4: TRAF3 as a gatekeeper for TNFR-induced stress kinase activation.
Figure 5: Differential TRAF3 ubiquitylation dictates the outcome of TLR4 signalling.
Figure 6: Role of TRAF3 in the regulation of NIK turnover and activity.

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Acknowledgements

We thank P. Mehta for the bioinformatics analysis of the TRAF domain structures depicted in Fig. 1. H.H. was supported by US National Institutes of Health (NIH) grant AI083443 and the American Lebanese Syrian Associated Charities (ALSAC). Work was also supported by NIH grant AI043477 to M.K., who is an American Cancer Society Research Professor.

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Authors and Affiliations

  1. Department of Infectious Diseases, St. Jude Childrens Research Hospital, Memphis, 38105, Tennessee, USA

    Hans Häcker

  2. Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan

    Ping-Hui Tseng

  3. Departments of Pharmacology and Pathology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California San Diego, La Jolla, 92093, California, USA

    Michael Karin

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Glossary

Inhibitor of apoptosis

A class of proteins (cIAP1, cIAP2, XIAP and NAIP) that contain BIR domains and that can act under certain conditions as intracellular caspase inhibitors. For cIAP1 and cIAP2 function in TNFR-associated factor (TRAF)-dependent signal transduction pathways, this function is probably not relevant.

E3 ubiquitin ligases

Enzymes that attach ubiquitin to substrate proteins. Single-subunit E3 ubiquitin ligases contain both the substrate-binding domain(s) and E2 tranferase recruitment machinery in the same polypeptide chain, whereas multisubunit E3 ubiquitin ligases divide these functions between individual protein components. E3 ubiquitin ligases are further classified on the basis of their E2 transferase recruitment domains, which can be HECT-type, RING finger-type or U box-type.

Mitogen-activated protein kinase

(MAPK). MAPKs are a group of serine/threonine-specific protein kinases that are activated by a variety of stimuli, including growth factors, cytokines, ionizing radiation and osmotic shock. MAPK activation is controlled through defined kinase cascades, which include a MAPK kinase (MAPKK) and a MAPKK kinase (MAP3K). These MAPK cascades serve as information relays, connecting different sensor molecules (such as cell surface receptors) to specific regulatory proteins (including transcription factors), thereby translating changes in the cell environment into gene regulation.

Alternative NF-κB pathway

A nuclear factor-κB (NF-κB) activation pathway that is activated by a subset of TNF receptor family members, including BAFFR, LTβR and CD40. In contrast to the classic NF-κB pathway, which depends on the catalytic activity of IκB kinase-β (IKKβ), the alternative pathway depends on the catalytic activity of IKKα, which phosphorylates p100 (also known as NF-κB2). This results in limited proteolytic processing of the C-terminal part of p100, thereby liberating the N-terminal active transcription factor p52. p52, together with its dimerization partner RELB, enters the nucleus and drives transcription.

Ubiquitylation

The attachment of the small protein ubiquitin to (primarily) lysine residues in other proteins. 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 C terminus of ubiquitin and an amino group belonging to a lysine residue of the target protein.

Proteasome

A giant multicatalytic protease resident in the cytosol and the nucleus. The 20S core, which contains three distinct catalytic subunits, can be appended at either end by a 19S cap or an 11S cap. The binding of two 19S caps to the 20S core forms the 26S proteasome, which degrades polyubiquitylated proteins.

Plasmacytoid dendritic cells

(pDCs). A subset of DCs that are described as plasmacytoid because their microscopic appearance resembles that of plasmablasts. On a per cell basis, pDCs are the main producers of type I interferons in response to virus infections or Toll-like receptor stimulation.

Plasma cells

Non-dividing, terminally differentiated, immunoglobulin-secreting cells of the B cell lineage.

SCFβTrCP

A multiprotein complex containing a protein core of SKP1, CUL1 and an F-box protein (the SCF complex) that catalyses the ubiquitylation of specific proteins destined for proteasomal degradation. β-transducin repeat-containing protein (βTrCP) is an F-box protein that recognizes specific phosphorylated substrates, including NK-κB inhibitor-α (IκBα) and p100 (also known as NK-κB2).

Herpes simplex encephalitis

Herpes simplex encephalitis is a rare complication of herpes simplex virus 1 (HSV-1) infection and has been associated with the impairment of innate immunity to HSV-1.

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Häcker, H., Tseng, PH. & Karin, M. Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol 11, 457–468 (2011). https://doi.org/10.1038/nri2998

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