Lack of XBP-1 impedes murine cytomegalovirus gene expression

• Published in: PloS one 2014-10, Vol.9 (10), p.e110942-e110942
• Main Authors: Drori, Adi, Messerle, Martin, Brune, Wolfram, Tirosh, Boaz
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Bacterial infections; Biology and Life Sciences; Cell cycle; Cytomegalovirus; Delay; DNA-Binding Proteins - genetics; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum Stress - genetics; Fibroblasts; Fibroblasts - pathology; Fibroblasts - virology; Gene expression; Gene Expression Regulation; Genetic engineering; Genomes; Health aspects; Homeostasis; Humans; Immunoglobulins; Infection; Infections; Kinases; Macrophages; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Metabolism; Mice; Muromegalovirus - genetics; Muromegalovirus - pathogenicity; Nuclei; Pathogenesis; Peritoneum; Phenotypes; Protein binding; Protein folding; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Regulatory Factor X Transcription Factors; RNA; RNA, Messenger - biosynthesis; Signaling; Splicing; Stress; Stresses; Transcription factors; Transcription Factors - genetics; Unfolded Protein Response - genetics; Viral infections; Virology; Virus Replication - genetics; X-Box Binding Protein 1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110942

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.