Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

cGAS is well established to be a DNA sensor, and unlike the case for IFI16, there is mechanistic understanding of how cGAS links to STING-dependent signaling, through production of the second messenger cGAMP as described above. 56, 57 The Kaposi's sarcoma-associated herpesvirus (KSHV) protein ORF52 was recently identified to inhibit the enzymatic activity of cGAS. ORF52 is like HCMV pUL83 a tegument protein, but contrary to the nuclear localization of pUL83, ORF52 is only found in the cytosol and in perinuclear regions. 58 ORF52 was reported to be a DNA-binding protein and the ability to sequester stimulatory DNA was shown to be important, but not sufficient for the KSHV-dependent inhibition of type I IFN. This observation was explained by cGAS binding to DNA occurring with higher affinity than DNA binding by ORF52. To complete the inhibition of cGAS, ORF52 is also able to bind cGAS directly. 59 The ORF52 homologs of three other gammaherpesviruses, namely Epstein-Barr virus, MHV68 and Rhesus monkey rhadinovirus are also able to bind cytosolic DNA and thus inhibit the enzymatic activity of cGAS, indicating that the cGAS target is evolutionary conserved in gammaherpesviruses. An ORF52-like protein encoded by an alphaherpesvirus, with a cGAS inhibitory function has not been reported. However, it has been speculated that the tegument protein VP22 from HSV-1 binds cGAS, as VP22 and ORF52 have some three dimensional structurally homology, 59,60 but functionally evidence is still lacking.