Endoplasmic reticulum (ER) stress response is mediated by dissociating with binding immunoglobulin protein (Bip) and controls cell fate. ER stress leads to the gene expression such as ATF4 and C/EBP homologous protein (CHOP).
B cell receptor (BCR) signaling is a physiologic ER stress trigger, induces gammaherpesvirus lytic replication, and serves as a physiological mechanism for gammaherpesvirus reactivation in infected B cells in vivo.
The researchers from Institut Pasteur of Shanghai, CAS used gammaherpesvirus mouse model murine gammaherpesvirus MHV68 to demonstrate that ER stress inhibited BCR-mediated gammaherpesvirus lytic replication by inducing Bip expression in associated lymphoma B cells. ER stress-induced transcription factor ATF4 directly inhibited promoter activity of viral lytic switch transactivator RTA and inhibited BCR-mediated gammaherpesvirus lytic gene expression.
However, ER stress-induced CHOP was required for and promoted BCR-mediated gammaherpesvirus lytic replication by suppressing Bip and ATF4 expression. These data suggest that ER stress and BCR signaling pathways are interconnected and form a complex network to regulate the gammaherpesvirus infection cycle, it sheds light on a complex physiological scenario for the regulation of gammaherpesvirus latency and lytic cycle in vivo.