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

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 su