1. Regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress-induced transcription factors ATF4 and CHOP.
- Author
-
Zhou XC, Dong SH, Liu ZS, Liu S, Zhang CC, and Liang XZ
- Subjects
- Activating Transcription Factor 4 antagonists & inhibitors, Activating Transcription Factor 4 genetics, Animals, Antiviral Agents pharmacology, B-Lymphocytes drug effects, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Line, Transformed, Endoplasmic Reticulum Chaperone BiP, Gammaherpesvirinae drug effects, Gammaherpesvirinae growth & development, Gene Expression Regulation drug effects, Gene Knockout Techniques, Heat-Shock Proteins antagonists & inhibitors, Heat-Shock Proteins genetics, Lysogeny drug effects, Mice, Molecular Chaperones antagonists & inhibitors, Molecular Chaperones genetics, Molecular Chaperones metabolism, Promoter Regions, Genetic drug effects, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, Thapsigargin pharmacology, Transcription Factor CHOP antagonists & inhibitors, Transcription Factor CHOP genetics, Tunicamycin pharmacology, Viral Proteins antagonists & inhibitors, Viral Proteins genetics, Viral Proteins metabolism, Virus Activation drug effects, Virus Replication drug effects, Activating Transcription Factor 4 metabolism, B-Lymphocytes virology, Endoplasmic Reticulum Stress drug effects, Gammaherpesvirinae physiology, Heat-Shock Proteins metabolism, Receptors, Antigen, B-Cell agonists, Transcription Factor CHOP metabolism
- Abstract
The stress-induced unfolded protein response (UPR) in the endoplasmic reticulum (ER) involves various signaling cross-talks and controls cell fate. B-cell receptor (BCR) signaling, which can trigger UPR, induces gammaherpesvirus lytic replication and serves as a physiological mechanism for gammaherpesvirus reactivation in vivo However, how the UPR regulates BCR-mediated gammaherpesvirus infection is unknown. Here, we demonstrate that the ER stressors tunicamycin and thapsigargin inhibit BCR-mediated murine gammaherpesvirus 68 (MHV68) lytic replication by inducing expression of the UPR mediator Bip and blocking activation of Akt, ERK, and JNK. Both Bip and the downstream transcription factor ATF4 inhibited BCR-mediated MHV68 lytic gene expression, whereas UPR-induced C/EBP homologous protein (CHOP) was required for and promoted BCR-mediated MHV68 lytic replication by suppressing upstream Bip and ATF4 expression. Bip knockout was sufficient to rescue BCR-mediated MHV68 lytic gene expression in CHOP knockout cells, and this rescue was blocked by ectopic ATF4 expression. Furthermore, ATF4 directly inhibited promoter activity of the MHV68 lytic switch transactivator RTA. Altogether, we show that ER stress-induced CHOP inhibits Bip and ATF4 expression and that ATF4, in turn, plays a critical role in CHOP-mediated regulation of BCR-controlled MHV68 lytic replication. We conclude that ER stress-mediated UPR and BCR signaling pathways are interconnected and form a complex network to regulate the gammaherpesvirus infection cycle., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2018
- Full Text
- View/download PDF