Abstract
The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-to-nucleus signaling cascade induced in response to ER stress. The UPR aims at restoring homeostasis, but can also induce apoptosis if stress persists. Infection by human and murine cytomegaloviruses (CMVs) provokes ER stress and induces the UPR. However, both CMVs manipulate the UPR to promote its prosurvival activity and delay apoptosis. The underlying mechanisms remain largely unknown. Recently, we demonstrated that MCMV and HCMV encode a late protein to target IRE1 for degradation. However, the importance of its downstream effector, X Box binding protein 1 (XBP-1), has not been directly studied. Here we show that deletion of XBP-1 prior to or early after infection confers a transient delay in viral propagation in fibroblasts that can be overcome by increasing the viral dose. A similar phenotype was demonstrated in peritoneal macrophages. In vivo, acute infection by MCMV is reduced in the absence of XBP-1. Our data indicate that removal of XBP-1 confers a kinetic delay in early stages of MCMV infection and suggest that the late targeting of IRE1 is aimed at inhibiting activities other than the splicing of XBP-1 mRNA.
Highlights
Cytomegalovirus (CMV) is the prototype member of the bherpesvirus subfamily (b-Herpesvirinae), harboring a linear double stranded DNA genome
We found that the ratio between phosphorylated and total eIF2a was comparable between WT and X Box binding protein 1 (XBP-1) KO cells, suggesting that global protein synthesis is not attenuated in the KO cells, probably due to adaptation to the chronic endoplasmic reticulum (ER) stress conditions (Fig. 1F)
The unfolded protein response (UPR) may serve to the advantage of the host by promoting the production of antiviral cytokines such as interferons and proinflammatory responses, such as the NF-kb pathway [50], and directing the infected cells to apoptosis through the ER stress pathway
Summary
Cytomegalovirus (CMV) is the prototype member of the bherpesvirus subfamily (b-Herpesvirinae), harboring a linear double stranded DNA genome. Both HCMV and MCMV target PERK-ATF4 and IRE1-XBP-1 pathways to selectively activate a subset of UPR genes [31]. Owing to the multifaceted roles played by IRE1 following activation, which include the splicing of XBP-1 mRNA, RIDD, JNK activation and triggering innate immunity sensors [34], it is not clear which of all of these have the potential to affect viral propagation in infected cells. This can be address by investigating the specific roles of the elements downstream to IRE1. We rigorously explored the role of XBP-1 in MCMV infection in vitro and in vivo
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