Figure 1: Schematic model forIRF5 activation. Cells use TLRs as sensors to detect the presence of viruses (V) via TLR7, -8, and -9. Alternatively, apoptotic debris (shown here as membrane blebs, ssRNA, and dsDNA) can also be a source of nuclear proteins and nucleic acids. Nuclear material is brought to the endosome, triggering TLR7, -8, and -9 signaling. Binding of cognate ligands to these TLRs recruits MyD88, a main signaling intermediate involved in TLR7, -8, and -9 signaling. MyD88 recruits interleukin-1 receptor associated kinase (IRAK)-4. IRAK-4 binds and phosphorylates IRAK-1, which in turn recruits Tumor necrosis factor (TNF) receptor associated factor (TRAF) 6 [4648]. TRAF6 is an E3 ubiquitin (Ub) ligase that adds K63-Ub chains to IRF5 [49]. IRF5 is then shuttled to the nucleus and is acetylated by CBP and p300 [50]. Together, these events set the stage for the transcription of IFN-α and other pro-inflammatory cytokine genes.