Title Varicella‑Zoster Virus ORF39 Transmembrane Protein Suppresses Interferon‑Beta Promoter Activation by Interacting with STING
Author Gwang Myeong Lee1, Shuang Gong1, Seong‑Wook Seo2, Hyemin Ko1, Woo‑Chang Chung1, Jihyun Lee1, Ok Sarah Shin2*, and Jin‑Hyun Ahn1,3*
Address 1Department of Microbiology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea, 2Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul 08308, Republic of Korea, 3Samsung Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
Bibliography Journal of Microbiology, 61(2),259-270, 2023,
DOI 10.1007/s12275-023-00019-7
Key Words VZV · ORF39 · STING · Interferon
Abstract 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.