Signaling from LMP1 and TLR to IRF7 activation. Shown is a scheme of the signaling cascade from LMP1 or TLR to activation of IRF7. LMP1 recruits TRAF6 through TRAF2. The latter protein may act as an E3 ligase for K63-linked ubiquitination of RIP1, which is required for downstream ubiquitination of IRF7 by TRAF6. TLR7/9 recruits TRAF6 through the adaptor protein MyD88. Although RIP1 is not required for TLR3/4 signaling for activation of IRF3 (), it may be involved in TLR3 signaling leading to IRF7 activation (Michelle Kelliher, personal communication). After recruitment, TRAF6 is auto-ubiquitinated and activated upon dimerization or oligomerization. Then, TRAF6 ubiquitinates and activates IRF7 through K63-Ub chains (pathway 1), which may recruit an IRF7 kinase (IKKα, IKKɛ, TANK-binding kinase 1, or IL-1 receptor-associated kinase 1) for IRF7 phosphorylation. And TRAF6-mediated ubiquitination may also regulate the activity of an IRF7 kinase (pathway 2). Solid arrows indicate regulatory pathways identified, and dashed arrows indicate pathways which are proposed but still under study. P, phosphorylated.
TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1 . (2008)
Shunbin Ning, et al. Mol Cell Biol. 2008 Oct;28(20):6536-6546. Figure: F9.
