Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

The family of herpesviruses has been reported to evade the DNA sensing machinery both at the level of sensing, and signaling through the STING-TBK1-dependent pathway. We previously identified a conserved herpesvirus deubiquitinase to inhibit STING-dependent DNA signaling in macrophages. 49 Mechanistically, this occurred upstream of DNA release into the cytosol, thus suggesting the deubiquitinase to prevent the viral DNA to become accessible for DNA sensors (Figure 3 ). The infected cell protein (ICP)0 protein encoded by HSV-1 possesses E3 ubiquitin ligase activity through the RING finger domain. The ubiquitination activity and an active proteasomal pathway was reported to be crucial for the establishment of lytic infection in HSV-1 infected cells. 50, 51 Orzalli et al. 35 reported ICP0 to trigger the degradation of IFI16 by the proteasome resulting in impaired sensing of HSV-1 and reduced production of IFN-stimulated genes. However, ICP0 also has functions independent of the E3 ligase activity. For instance, ICP0 was found to inhibit IRF3 in the nucleus of epithelial cells co-infected with HSV-1 and Sendai virus. 52 This was due to sequestration of IRF-3 in ICP0-containing foci in the nucleus, thus resulting in a dislocation of the transcription factor away from the promoter target elements. 35 Another herpesvirus protein known to target IFI16 is pUL83, a tegument protein of human CMV (HCMV). pUL83 is the most abundant protein in the HCMV particle and the protein localizes to the nucleus early during infection. 53, 54 pUL83 was first shown to interact with nuclear IFI16 to stimulate IFI16dependent transcription from the major immediate-early promoter of HCMV. 55 In a follow-up work by Li et al., 36 pUL83 was reported to inhibit the oligomerization of activated, nuclear IFI16 and hence to block the signal transmission from IFI16 to STING resulting in diminished type I IFN expression. The work showed pUL83 to interact directly with the Pyrin domain of IFI16, with inhibitory effects. The Pyrin domain has been reported to be essential for cooperative assembly of IFI16 filaments on dsDNA, 29 which is likely to be a requirement for IFI16-mediated DNA dependent signaling. The results on ICP0 and pUL83 underline that IFI16 takes part in sensing of herpesvirus genomes and activates a STING-dependent type I IFN signaling pathway. Despite this, there is currently no mechanistic understanding of how IFI16 mediates activation of the STING pathway.