Ubiquitin in the activation and attenuation of innate antiviral immunity

Heaton, Steven M.; Borg, Natalie A.; Dixit, Vishva M.

Both TRIM25 and RNF135 are targets of the influenza A virus (IAV) nonstructural protein 1 (NS1), which blocks their E3 activity and ubiquitin-dependent RIG-I activation ( Fig. 3 ; Gack et al., 2009; Rajsbaum et al., 2012) . IAV-NS1 binds the central coiled-coil domain (CCD) of TRIM25 and is postulated to prevent CCD-mediated homooligomerization. Although the NS1-binding site on RNF135 is unknown, RNF135 and TRIM25 share a similar RING-CCD-B30.2/SPRY (sp1A and ryanodine receptors) domain Figure 2 . Schematic of the TLR, RLR, and NLR antiviral protein signaling cascades and modes of cross-talk. PRRs (blue) screen the intracellular and extracellular environment for pathogenic motifs. Ligand-activated PRRs bind adaptor proteins (purple) and recruit protein kinases (yellow) and ubiquitin-protein ligases (green). These regulate immune signal transduction to transcription factors (orange) through PTM of signaling cascade proteins. Other regulatory proteins (gray) support or sequester these signaling proteins. Immune signaling scaffolds such as mitochondria typically coordinate these actions. Activated transcription factors translocate into the nucleus and bind to promoter response elements, stimulating appropriate antiviral gene transcription. Blue and green circles represent ubiquitination and phosphorylation, respectively. Black arrows, activation; red lines, deactivation.