1. Academic Validation
  2. The mTOR inhibitor manassantin B reveals a crucial role of mTORC2 signaling in Epstein-Barr virus reactivation

The mTOR inhibitor manassantin B reveals a crucial role of mTORC2 signaling in Epstein-Barr virus reactivation

  • J Biol Chem. 2020 May 22;295(21):7431-7441. doi: 10.1074/jbc.RA120.012645.
Qian Wang 1 Nannan Zhu 1 Jiayuan Hu 1 Yan Wang 2 Jun Xu 3 Qiong Gu 3 Paul M Lieberman 4 Yan Yuan 5
Affiliations

Affiliations

  • 1 Institute of Human Virology, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 2 Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 3 School of Pharmacy, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 4 The Wistar Institute, Philadelphia, Pennsylvania 19104.
  • 5 Institute of Human Virology, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104. Electronic address: yuan2@upenn.edu.
Abstract

Lytic replication of Epstein-Barr virus (EBV) is not only essential for its cell-to-cell spread and host-to-host transmission, but it also contributes to EBV-induced oncogenesis. Thus, blocking EBV lytic replication could be a strategy for managing EBV-associated diseases. Previously, we identified a series of natural Lignans isolated from the roots of Saururus chinensis (Asian lizard's tail) that efficiently block EBV lytic replication and virion production with low cytotoxicity. In this study, we attempted to elucidate the molecular mechanism by which these Lignans inhibit EBV lytic replication. We found that a representative compound, CSC27 (manassantin B), inhibits EBV lytic replication by suppressing the expression of EBV immediate-early gene BZLF1 via disruption of AP-1 signal transduction. Further analysis revealed that manassantin B specifically blocks the mammalian target of rapamycin complex 2 (mTORC2)-mediated phosphorylation of Akt Ser/Thr protein kinase at Ser-473 and protein kinase Cα (PKCα) at Ser-657. Using phosphoinositide 3-kinase-AKT-specific inhibitors for kinase mapping and shRNA-mediated gene silencing, we validated that manassantin B abrogates EBV lytic replication by inhibiting mTORC2 activity and thereby blocking the mTORC2-PKC/AKT-signaling pathway. These results suggest that mTORC2 may have utility as an Antiviral drug target against EBV infections and also reveal that manassantin B has potential therapeutic value for managing cancers that depend on mTORC2 signaling for survival.

Keywords

EBV reactivation; Epstein-Barr virus (EBV); inhibition mechanism; inhibitor; lignan; mTOR complex (mTORC); mTORC2 inhibitor; manassantin B; protein kinase C (PKC); viral DNA; viral replication; virology.

Figures
Products