The epstein-barr virus lytic protein bmlf1 induces upregulation of grp78 expression through atf6 activation

Lee Wen Chen, Shie Shan Wang, Chien Hui Hung, Ya Hui Hung, Chun-Liang Lin, Pey Jium Chang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations


The unfolded protein response (UPR) is an intracellular signaling pathway essential for alleviating the endoplasmic reticulum (ER) stress. To support the productive infection, many viruses are known to use different strategies to manipulate the UPR signaling network. However, it remains largely unclear whether the UPR signaling pathways are modulated in the lytic cycle of Epstein-Barr virus (EBV), a widely distributed human pathogen. Herein, we show that the expression of GRP78, a central UPR regulator, is up-regulated during the EBV lytic cycle. Our data further revealed that knockdown of GRP78 in EBV-infected cell lines did not substantially affect lytic gene expression; however, GRP78 knockdown in these cells markedly reduced the production of virus particles. Importantly, we identified that the early lytic protein BMLF1 is the key regulator critically contributing to the activation of the grp78 gene promoter. Mechanistically, we found that BMLF1 can trigger the proteolytic cleavage and activation of the UPR senor ATF6, which then transcriptionally activates the grp78 promoter through the ER stress response elements. Our findings therefore provide evidence for the connection between the EBV lytic cycle and the UPR, and implicate that the BMLF1-mediated ATF6 activation may play critical roles in EBV lytic replication.

Original languageEnglish
Article number4024
JournalInternational Journal of Molecular Sciences
Issue number8
StatePublished - 02 04 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • ATF6
  • BMLF1
  • Epstein-Barr virus
  • GRP78
  • Lytic replication
  • Unfolded protein response


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