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.
Highlights
The stress-induced unfolded protein response (UPR) in the endoplasmic reticulum (ER) involves various signaling crosstalks and controls cell fate
The induction of the gammaherpesvirus lytic cycle is initiated by the activation of a conserved lytic switch gene, which is encoded by highly conserved immediately-early genes BRLF1 in Epstein-Barr virus (EBV) and ORF50 in Kaposi sarcoma– associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68)
We show that ER stress caused by TG and tunicamycin (TM) inhibited B-cell receptor (BCR)-mediated MHV68 viral DNA replication and lytic gene expression in MHV68-immortalized SL-1 lymphoma B cells concomitantly with the inhibition of constitutive Akt, extracellular signal–regulated kinases (ERK), and Jun N-terminal kinases (JNK) activation after prolonged TG or TM treatment preceded by binding immunoglobulin protein (Bip) and C/EBP homologous protein (CHOP) induction
Summary
ER stress differentially regulates gammaherpesvirus lytic replication, such as the ER stress inducer thapsigargin (TG), which inhibits ER Ca2ϩ-ATPase from recovering luminal ER calcium stores [30], triggers EBV lytic replication in lymphoblastoid cell lines [31], whereas the induction of ER stress by 2-deoxy-D-glucose inhibits KSHV and MHV68 lytic gene expression [32]. We show that ER stress caused by TG and tunicamycin (TM) inhibited BCR-mediated MHV68 viral DNA replication and lytic gene expression in MHV68-immortalized SL-1 lymphoma B cells concomitantly with the inhibition of constitutive Akt, ERK, and JNK activation after prolonged TG or TM treatment preceded by Bip and CHOP induction. ATF4 directly inhibited RTA promoter activity, suppressed BCR-mediated MHV68 lytic gene expression, and correspondingly contributed to the regulatory role of CHOP in BCR-mediated MHV68 lytic replication
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
