Varicella-Zoster virus (VZV) causes varicella in primary infection of children and zoster during reactivation in adults. Type
I interferon (IFN) signaling suppresses VZV growth, and stimulator of interferon genes (STING) plays an important role
in anti-VZV responses by regulating type I IFN signaling. VZV-encoded proteins are shown to inhibit STING-mediated
activation of the IFN-β promoter. However, the mechanisms by which VZV regulates STING-mediated signaling pathways
are largely unknown. In this study, we demonstrate that the transmembrane protein encoded by VZV open reading frame
(ORF) 39 suppresses STING-mediated IFN-β production by interacting with STING. In IFN-β promoter reporter assays,
ORF39 protein (ORF39p) inhibited STING-mediated activation of the IFN-β promoter. ORF39p interacted with STING in
co-transfection assays, and this interaction was comparable to that of STING dimerization. The cytoplasmic N-terminal 73
amino acids region of ORF39P was not necessary for ORF39 binding and suppression of STING-mediated IFN-β activation.
ORF39p also formed a complex containing both STING and TBK1. A recombinant VZV expressing HA-tagged ORF39
was produced using bacmid mutagenesis and showed similar growth to its parent virus. During HA-ORF39 virus infection,
the expression level of STING was markedly reduced, and HA-ORF39 interacted with STING. Moreover, HA-ORF39 also
colocalized with glycoprotein K (encoded by ORF5) and STING at the Golgi during virus infection. Our results demonstrate
that the transmembrane protein ORF39p of VZV plays a role in evading the type I IFN responses by suppressing STINGmediated
activation of the IFN-β promoter.