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Review
. 2011 Nov;244(1):55-74.
doi: 10.1111/j.1600-065X.2011.01055.x.

Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions

Joanne M Hildebrand  1 , Zuoan Yi, Claire M Buchta, Jayakumar Poovassery, Laura L Stunz, Gail A Bishop
Affiliations
Review

Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions

Joanne M Hildebrand et al. Immunol Rev. 2011 Nov.

Abstract

A large and diverse group of receptors utilizes the family of cytoplasmic signaling proteins known as tumor necrosis factor receptor (TNFR)-associated factors (TRAFs). In recent years, there has been a resurgence of interest and exploration of the roles played by TRAF3 and TRAF5 in cellular regulation, particularly in cells of the immune system, the cell types of focus in this review. This work has revealed that TRAF3 and TRAF5 can play diverse roles for different receptors even in the same cell type, as well as distinct roles in different cell types. Evidence indicates that TRAF3 and TRAF5 play important roles beyond the TNFR-superfamily (SF) and viral mimics of its members, mediating certain innate immune receptor and cytokine receptor signals, and most recently, signals delivered by the T-cell receptor (TCR) signaling complex. Additionally, much research has demonstrated the importance of TRAF3-mediated cellular regulation via its cytoplasmic interactions with additional signaling proteins. In particular, we discuss below evidence for the participation by TRAF3 in a number of the regulatory post-translational modifications involving ubiquitin that are important in various signaling pathways.

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Conflict of interest statement

The authors declare no financial or commercial conflict of interest.

Figures

Fig. 1
Fig. 1. Different modes of TRAF3 ubiquitination lead to diverse signaling outcomes
Controlled TRAF3 -interferon production following TLR and RLR activation occurs in two phases. (A) Soon after receptor activation, TRAF3 undergoes K63 linked ubiquitination and facilitates the recruitment and activity of downstream kinases including IRF3. (B) After several hours, the production of K63 de-ubiquitinases and K48 E3 ubiquitin ligases lead to TRAF3 complex dissolution and TRAF3 destruction, halting further interferon production. (C) TLR stimulation and CD40 activation also facilitate pro-inflammatory cytokine production, a process that requires rapid TRAF3 recruitment and K48 mediated proteasomal degradation for the liberation of cytoplasmic MAPK-activating complexes. (D) TRAF3’s role in constitutive suppression of NF-κB2 through NIK degradation ends following recruitment to some TNFR-SF members. cIAP1/2 mediated K48 ubiquitination of TRAF3 leads to NIK stabilization and NF-κB2 activation.
See this image and copyright information in PMC

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