- Varicella‑Zoster Virus ORF39 Transmembrane Protein Suppresses Interferon‑Beta Promoter Activation by Interacting with STING
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Gwang Myeong Lee , Shuang Gong , Seong&# , Hyemin Ko , Woo&# , Jihyun Lee , Ok Sarah Shin , Jin&#
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J. Microbiol. 2023;61(2):259-270. Published online February 20, 2023
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DOI: https://doi.org/10.1007/s12275-023-00019-7
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 Abstract
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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.
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Citations
Citations to this article as recorded by  - Genomic comparison reveals single-nucleotide polymorphic sites and attenuation-associated site combinations specific to Chinese live attenuated varicella-zoster virus vaccines
Yuchan Zhang, Xuhua Duan, Yuanyuan Cai, Mingren Wang, Ziqiang Wang, Minghui Song, Tianyi Qiu, Xuanyi Wang, Hong Shao
Human Vaccines & Immunotherapeutics.2026;[Epub] CrossRef - Antiviral effects of heme oxygenase-1 against canine coronavirus and canine influenza virus in vitro
Jae-Hyeong Kim, Dong-Hwi Kim, Kyu-Beom Lim, Joong-Bok Lee, Seung-Yong Park, Chang-Seon Song, Sang-Won Lee, Dong-Hun Lee, Do-Geun Kim, Hun-Young Yoon, In-Soo Choi
Journal of Microbiology.2025; 63(5): e2501029. CrossRef
- Analysis of IE62 mutations found in Varicella-Zoster virus vaccine strains for transactivation activity
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Hyemin Ko , Gwang Myeong Lee , Ok Sarah Shin , Moon Jung Song , Chan Hee Lee , Young Eui Kim , Jin-Hyun Ahn
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J. Microbiol. 2018;56(6):441-448. Published online June 1, 2018
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DOI: https://doi.org/10.1007/s12275-018-8144-x
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967
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Abstract
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Live attenuated vaccine strains have been developed for Varicella-
Zoster virus (VZV). Compared to clinically isolated
strains, the vaccine strains contain several non-synonymous
mutations in open reading frames (ORFs) 0, 6, 31, 39, 55, 62,
and 64. In particular, ORF62, encoding an immediate-early
(IE) 62 protein that acts as a transactivator for viral gene
expression, contains six non-synonymous mutations, but
whether these mutations affect transactivation activity of
IE62 is not understood. In this study, we investigated the
role of non-synonymous vaccine-type mutations (M99T,
S628G, R958G, V1197A, I1260V, and L1275S) of IE62 in
Suduvax, a vaccine strain isolated in Korea, for transactivation
activity. In reporter assays, Suduvax IE62 showed 2- to
4-fold lower transactivation activity toward ORF4, ORF28,
ORF29, and ORF68 promoters than wild-type IE62. Introduction
of individual M99T, S628G, R958G, or V1197A/
I1260V/L1275S mutations into wild-type IE62 did not affect
transactivation activity. However, the combination of M99T
within the N-terminal Sp transcription factor binding region
and V1197A/I1260V/L1275S within the C-terminal serineenriched
acidic domain (SEAD) significantly reduced the
transactivation activity of IE62. The M99T/V1197A/I1260V/
L1275S mutant IE62 did not show considerable alterations
in intracellular distribution and Sp3 binding compared to
wild-type IE62, suggesting that other alteration(s) may be
responsible for the reduced transactivation activity. Collectively,
our results suggest that acquisition of mutations in
both Met 99 and the SEAD of IE62 is responsible for the reduced
transactivation activity found in IE62 of the VZV
vaccine strains and contributes to attenuation of the virus.
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Citations
Citations to this article as recorded by - Genomic comparison reveals single-nucleotide polymorphic sites and attenuation-associated site combinations specific to Chinese live attenuated varicella-zoster virus vaccines
Yuchan Zhang, Xuhua Duan, Yuanyuan Cai, Mingren Wang, Ziqiang Wang, Minghui Song, Tianyi Qiu, Xuanyi Wang, Hong Shao
Human Vaccines & Immunotherapeutics.2026;[Epub] CrossRef - Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation
Ji-Soo Lim, Soo-Jin Oh, Ji-Yeun Hur, Subin Oh, Seuk-Min Ryu, Rafael T. Han, Hosun Park, Dawn M. E. Bowdish, Ok Sarah Shin
Journal of Biomedical Science.2026;[Epub] CrossRef - Heightened incidence of adverse events associated with a live attenuated varicella vaccine strain that lacks critical genetic polymorphisms in open reading frame 62
Ye Ji Kim, Doyeop Oh, Jaehoon Kim, Jeongtae Son, Jae Yun Moon, Ye Kyung Kim, Bin Ahn, Kyu Ri Kang, Daechan Park, Hyun Mi Kang
Clinical Microbiology and Infection.2024; 30(11): 1466. CrossRef - Whole Transcriptome Analyses Reveal Differential mRNA and microRNA Expression Profiles in Primary Human Dermal Fibroblasts Infected with Clinical or Vaccine Strains of Varicella Zoster Virus
Soo-Jin Oh, Sooyeon Lim, Moon Jung Song, Jin Hyun Ahn, Chan Hee Lee, Ok Sarah Shin
Pathogens.2019; 8(4): 183. CrossRef
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