Gammaherpesviruses, including Epstein-Barr virus (EBV), are important human pathogens because they are associated with various tumors. Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional host nuclear protein responsible for poly (ADP-ribosyl)ation (PARylation) of target proteins. While PARP1 acts as a negative regulator that suppresses the lytic replication of gammaherpesviruses, viruses are often equipped with various strategies to overcome PARP1 inhibition. However, the mechanisms of how EBV may modulate a repressive host protein, PARP1, are still elusive. In this study, we found that EBV reactivation induced PARP1 downregulation in EBV-infected cells. EBV DNA polymerase processivity factor EA-D, encoded by the BMRF1 gene, directly interacted with the central automodification domain (AD) of PARP1 and was necessary and sufficient to downregulate PARP1 via K29-linked polyubiquitination. Moreover, knockdown of EA-D in B95.8 cells restored PARP1 levels and abrogated the expression of ZTA (also known as ZEBRA), a switch molecule of the EBV life cycle during reactivation. Interestingly, PARP1 PARylated RTA, another key switch molecule, and decreased RTA transactivation on the promoters of the ZTA, BMRF1, and BMLF1 genes. EA-D alleviated the PARylation of RTA and further enhanced RTA-mediated transactivation of these lytic promoters in reporter assays. Taken together, our results suggest that EBV viral processivity factor plays a key role in facilitating lytic replication by inducing PARP1 degradation via its interaction with the PARP1 AD, which is a highly conserved mechanism among gammaherpesviruses to counteract host repressive activity of PARP1 against viral lytic replication.
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants, the Bio and Medical Technology Development Program, and the Basic Research Laboratory Program of NRF funded by the Republic of Korea government (MSIT) (2020R1A2C2013827, 2021M3A9I2080487, and 2020R1A4A1018019).
© 2022 American Society for Microbiology.
- Epstein-Barr virus
- lytic replication
- poly(ADP-ribose) polymerase 1
- proteasomal degradation
- viral processivity factor
ASJC Scopus subject areas
- Insect Science