Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function

Lijun Jiang, Hong Lok LUNG, Tao Huang, Rongfeng Lan, Shuai Zha, Lai Sheung Chan, Waygen Thor, Tik Hung Tsoi, Ho Fai Chau, Cecilia Boreström, Steven L. Cobb, Sai Wah Tsao, Zhaoxiang BIAN, Ga Lai Law, Wing Tak Wong, William C S TAI, Wai Yin Chau, Yujun Du, Lucas Hao Xi Tang, Alan Kwok Shing ChiangJaap M. Middeldorp, Kwok Wai Lo, Nai Ki MAK, Nicholas J. Long, Ka-Leung WONG*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV proteinspecific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

Original languageEnglish
Pages (from-to)26614-26624
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
DOIs
Publication statusPublished - 26 Dec 2019

Scopus Subject Areas

  • General

User-Defined Keywords

  • Dual-responsive fluorescent EBV probe
  • EBNA1-targeting agent
  • EBV-specific lytic inducer

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