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Review
. 2016 Nov;100(5):919-926.
doi: 10.1189/jlb.2MR0216-063R. Epub 2016 May 6.

TRAF3 as a powerful and multitalented regulator of lymphocyte functions

Gail A Bishop  1   2   3
Affiliations
Review

TRAF3 as a powerful and multitalented regulator of lymphocyte functions

Gail A Bishop. J Leukoc Biol. 2016 Nov.

Abstract

This review summarizes the current state of knowledge regarding the roles of the signaling adapter protein tumor necrosis factor receptor (TNFR)-associated factor 3 in regulating the functions of B and T lymphocytes. In B lymphocytes, TNFR-associated factor 3 inhibits signaling by TNFR superfamily receptors, Toll-like receptors, and interleukin-6R. In contrast, signaling to B cells by the virally encoded oncogenic protein latent membrane protein 1 is promoted by TNFR-associated factor 3. An important B cell-specific role for TNFR-associated factor 3 is the inhibition of homeostatic survival, directly relevant to the common occurrence of TNFR-associated factor 3 mutations in human B cell malignancies. TNFR-associated factor 3 was recently found to be a resident nuclear protein in B cells, where it interacts with and inhibits gene expression mediated by the cAMP response element-binding protein transcription complex, including expression of the prosurvival protein myeloid leukemia cell differentiation protein 1. In T lymphocytes, TNFR-associated factor 3 is required for normal signaling by the T cell antigen receptor, while inhibiting signaling by the interleukin-2 receptor. Cytoplasmic TNFR -associated factor 3 restrains nuclear factor-κB2 activation in both T and B cells. Clinical implications and future directions for the study of this context-dependent signaling regulator are discussed.

Keywords: B cell; T cell; signal transduction.

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Figures

Figure 1
Figure 1
TRAF family molecules. A schematic depiction of the basic structural features of the TRAF molecules. All except TRAF1 have an N‐terminal Zn‐binding RING domain, followed by a variable number of Zn finger motifs. The coiled‐coil/TRAF‐N domain allows TRAFs to form homo‐ or heteromultimers. All except TRAF7 have a C‐terminal TRAF‐C domain used to mediate many of their protein–receptor and protein–protein interactions. TRAF7 has a unique C‐terminal structure containing multiple WD40 domains [10]. TRAF4 and recently, TRAF3 are reported to have canonical NLS sequences [11, 12].
Figure 2
Figure 2
Mechanisms of TRAF3‐mediated lymphocyte regulation. Examples of the multiple ways in which TRAF3 influences lymphocyte activation events are illustrated. (Left to right) TRAF3 binds to the cytoplasmic domains of CD40 and BAFFR in B lymphocytes; in the case of CD40, TRAF3 competes with TRAF2 for this binding and inhibits TRAF2‐mediated activation events, such as canonical NF‐κB1 and JNK activation. Recruitment of TRAF2 and ‐3 to these receptors allows cIAP2 associated with TRAF2 to mediate polyubiquitination (indicated by ‘U’ in hexagons) and degradation of both TRAFs. Signaling by these receptors also impacts cytoplasmic TRAF3, which binds the kinase NIK and through recruitment of TRAF2–cIAP, mediates the ubiquitination and degradation of NIK. This limits NIK‐mediated NF‐κB activation. TRAF3 regulates cytokine Rs (IL‐6R in B cells and IL‐2R in T cells are discussed in the text) by binding to these Rs and Jak kinases and recruiting specific phosphatases (p'ase; PTPN22 to the IL‐6R, TCPTP to the IL‐2R), which dephosphorylate the Jaks, resulting in reduced downstream Stat phosphorylation (Stat‐p) and transcriptional activation. In B cells, nuclear TRAF3 binds the CREB transcriptional complex, recruiting TRAF2–cIAP to destabilize CREB, limiting CREB‐mediated transcription of prosurvival proteins. In T cells, TRAF3 associates with the TCR complex and enhances its signaling. One mechanism by which this occurs is the binding and cytoplasmic sequestration of Csk and PTPN22, allowing increased Lck activation. References are cited in the accompanying text.
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