Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP- Mediated IFN-beta Induction

Abstract

Stimulator of interferon genes (STING) is a critical signaling molecule in the innate immune response against DNA viruses by either directly sensing intracellular DNA or functioning as an adaptor molecule to activate the type I interferon (IFN) signaling pathway. We determined the functional interaction between STING and human cytomegalovirus (HCMV). A cDNA library containing 133 HCMV ORFs was screened to identify viral genes that inhibit STING-induced IFN-beta promoter activation. Among the screened ORFs, UL122, which encodes the immediate-early 2 86 kDa (IE86) protein, strongly abolished STING-induced IFN-b promoter activation. Interestingly, IE86 protein facilitated the proteasome-dependent degradation of STING and inhibited 2'3' -cGAMPmediated induction of IFNB1 and CXCL10. Taken together, this study demonstrates the existence of a post-translational regulation of STING by HCMV IE86 protein.