TRIF signaling activates TRAF3 self-mediated polyubiquitination trough Lys-63 of ubiquitin. The ubiquitinated TRAF3 in turn activates the interferon response (Tseng PH et al. 2010).

TRAF3 a E3 ligase for K63-linked polyubiquitination, is one of the critical molecules required for mediating IPS-1 dependent type I IFN production. TRAF3 interacts directly with IPS-1 through the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) with in IPS-1.

In the absence of BAFFR (TNFSF13C) ligation to BAFF (TNFSF13B) ligand, NFkB-inducing kinase (NIK) forms a complex with TNF receptor associated factor 3 (TRAF3) and TRAF2 which exists in a preassembled complex with cellular Inhibitor of apoptosis 1 (cIAP1) and cIAP2 in the cytosol. cIAP1/2 targets NIK for degradation by ubiquitylation, there by inhibiting non-canonical NFkB pathway (Vallabhapurapu et al. 2008, Zarnegar et al. 2008). Upon BAFF trimer binding to BAFFR, TRAF3 but not TRAF2 is recruited to the receptor via a 'PVPAT' binding site. This unique feature of BAFFR to recruit TRAF3 instead of TRAF2 is primarily due to its possession of an atypical TRAF-binding sequence (Morrison et al 2005). Following recruitment to BAFFR, TRAF3 undergoes proteasomal degradation, a process which requires TRAF2 and cIAP1/2.

OTUD5 (Deubiquitinating enzyme A (DUBA)) is a negative regulator of type I interferon (IFN-) production. TRAF3, an E3 ubiquitin ligase that preferentially assembles lysine-63-linked polyubiquitin chains, is one of the targets of OTUD5. Expression of DUBA increases the cleavage of K63-linked ubiquitin chains from TRAF3, resulting in its dissociation from the downstream signaling complex that contains TANK-binding kinase 1 (TBK1) (Kayagaki et al. 2007), which leads to blockade of IRF3 and IRF7 phosphorylation.

TNF Receptor Associated Factor 3 (TRAF3) is a cytoplasmic adaptor protein utilized by the tumor necrosis factor receptor superfamily and toll-like receptors (TLRs). TRAF3 deficiency is thought to mimic the previously reported TLR3 deficiency in terms of susceptibility to herpes simplex virus type 1 (HSV1) encephalitis (HSE) via impaired TLR3-mediated immunity against HSV1 infection of central nervous system (CNS) (Pérez de Diego R et al. 2010; Guo Y et al. 2011).

MAVS via its TRAF-interaction motif (TIM) directly interacts with TRAF3 and recruits TRAF3 to the signaling complex. TRAF3 acts as a scaffold for the assembly of a signaling complex composed of IKK epsilon/TBK1, leading to the activation of transcription factors IRF3/IRF7.

Activation of NF-kB is fundamental to signal transduction by members of the TNFRSF. Expression of NF-kB target genes is essential for mounting innate immune responses to infectious microorganisms but is also important for the proper development and cellular compartmentalization of secondary lymphoid organs necessary to orchestrate an adaptive immune response.
NF-kB transcription factor family is activated by two distinct pathways: the canonical pathway involving NF-kB1 and the non-canonical pathway involving NF-kB2. Unlike NF-kB1 signalling, which can be activated by a wide variety of receptors, the NF-kB2 pathway is typically activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor receptor (TNF) super family (TNFRSF) members. These members include TNFR2 (Rauert et al. 2010), B cell activating factor of the TNF family receptor (BAFFR also known as TNFRSF13C) (Kayagaki et al. 2002, CD40 (also known as TNFRSF5) (Coope et al. 2002, lymphotoxin beta-receptor (LTBR also known as TNFRSF3) (Dejardin et al. 2002), receptor activator for nuclear factor kB (RANK also known as TNFRSF11A) (Novack et al. 2003), CD27 and Fibroblast growth factor-inducible immediate-early response protein 14 (FN14 also known as TNFRSF12A) etc. These receptors each mediate specific biological roles of the non-canonical NF-kB. These non-canonical NF-kB-stimulating receptors have one thing in common and is the presence of a TRAF-binding motif, which recruits different TNF receptor-associated factor (TRAF) members, particularly TRAF2 and TRAF3, to the receptor complex during ligand ligation (Grech et al. 2004, Bishop & Xie 2007). Receptor recruitment of these TRAF members leads to their degradation which is a critical step leading to the activation of NIK and induction of p100 processing (Sun 2011, 2012).

TRAF6 is crucial for both RIG-I- and MDA5-mediated antiviral responses. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of type I IFNs and IL6 after infection with RNA virus. Activation of NF-kB and IRF7, but not that of IRF3, was significantly impaired during RIG-like helicases (RLHs) signaling in the absence of TRAF6. TRAF6-induced activation of IRF is likely to be specific for IRF7, while TRAF3 is thought to activate both IRF3 and IRF7. These results strongly suggest that the TRAF6- and TRAF3-dependent pathways are likely to bifurcate at IPS-1, but to converge later at IRF7 in order to co-operatively induce sufficient production of type I IFNs during RLH signaling.

TNF receptor-associated factor 3