Abstract

We previously reported that human cytomegalovirus (HCMV) 86 kDa immediate-early 2 gene product (IE86) promotes proteasome-dependent degradation of STING. In the present study, we determined the specific residues of IE86 responsible for STING degradation using a STING-firefly luciferase fusion protein expression system for quantitative measurement of STING protein levels. IE86 amino acids (aa) 136–289 were sufficient to promote STING degradation and further induced down-regulation of 2􍿁3􍿁-cyclic GMP-AMP (cGAMP)-mediated IFN-β promoter activation. Interestingly, transactivation domains (TAD) of the IE86 protein located at the N- and C-termini were required for down-regulation of Toll/interleukin-1 receptor (TIR) domain-containing adaptor- inducing interferon β (IFN-β) (TRIF)-mediated IFN-β- and p65/RelA-induced NF-κB-dependent promoter activation while amino acids (aa) 136–289 had no significant effects. Our collective data suggest that the IE86 protein utilizes the aa 136–289 region to promote STING degradation and inhibit the cGAS-STING pathway.

• Keywords: HCMV; IE86; STING; type I IFN