Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

Recently, a study aiming to identify novel KSHV-encoded proteins targeting DNA sensing pathways, reported that the viral IRF1 (vIRF1), interacted directly with STING, at a time point after STING trafficking from the ER. This interaction impedes the binding of TBK1 to STING, thus inhibiting phosphorylation and activation of STING, TBK1 and IRF3. 61 Consequently, vIRF1 was found to be able to inhibit the induction of type I IFN production. An additional role for vIRF1 in evasion of KSHV-induced IFN production has also been reported to occur through interaction between vIRF1 and the transcriptionally coactivators CBP/p300. The interaction impairs the association between CBP/p300 and IRF3 resulting in inefficient transcription from IRF3-dependent promoters. 62 Several herpesvirus proteins are reported to target TBK1 as a viral strategy to inhibit the DNA sensing pathway further downstream in the pathway. ICP34.5 from HSV-1 and ORF11 from MHV68 both bind directly to TBK1, resulting in decreased IRF3 activation and type I IFN expression. 63, 64 The KSHV protein ORF45 uses an alternative mechanism to inhibit TBK1-dependent type I IFN expression. ORF45 do not inactivate TBK1, but acts instead as an alternative substrate for TBK1. In a HEK293T cell system, ORF45 was found to interact with non-phosphorylated IRF7 and as ORF45 in this context is a preferred substrate for TBK1 compared with IRF7, ORF45 is phosphorylated on two serine residues in a TBK1-dependent manner whereas IRF7 remains non-phosphorylated and thus inactive. 65 This mechanism does not affect IRF3 activation but leads to decreased type I IFN expression, given the welldescribed role for IRF7 in the IFN-positive feedback loop. 66, 67 EVASION OF DNA-STIMULATED SIGNALING BY OTHER VIRUSES Although most information on evasion of DNA-stimulated signaling has been obtained from studies on herpesviruses, Viral evasion of innate immune responses MH Christensen and SR Paludan there is also accumulating evidence for other viruses targeting these pathways. For instance the Hepatitis B virus DNA polymerase interacts with STING, and inhibits production of type I IFNs. 68 The interaction between the two proteins prompted degradation of STING. Interestingly, the pool of STING that was degraded was ubiquitinated through K63linked chains, a process which has been reported to be mediated by several E3 ubiquitin ligases and to be essential for activation of the pathway. 1 Thus, the Hepatitis B virus DNA polymerase targets selectively the pool of activated STING. Several DNA oncoviruses express proteins that target the Leu-X-Cys-X-Glu (LXCXE) binding site in the retinoblastoma protein, thus contributing to the oncogenic properties of these viruses. 69 Additionally, the LXCXE motif was recently found to be important in the inhibition of the DNA sensing pathway by oncogenic viruses. The E7 protein from human papillomavirus and E1A from adenovirus were both identified as suppressors of the cGAS-STING pathway. 70 Interestingly, the LXCXE motif was reported to bind STING and inhibit downstream signaling. As many cell lines are immortalized with LXCXE-containing tumor proteins, the DNA sensing pathway of these cell lines is permanently impaired. Thus Lau et al. 70 showed that knock out of E1A and E7 increased the potential to mount type I IFN responses to dsDNA in these cell lines. LXCXE-containing proteins are expressed by different ssDNA and dsDNA viruses and potently bind the retinoblastoma protein, thus