Repression of viral gene expression and replication by the unfolded protein response effector XBP1u
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Germany
- San Raffaele Scientific Institute, Italy
- Institute for Drug Research, Israel
Abstract
The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (Xbp1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced Xbp1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 through 9.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (BR1730/6-1)
- Wolfram Brune
Horizon 2020 Framework Programme (ITN-TREATMENT grant 721236)
- Boaz Tirosh
German-Israeli Foundation for Scientific Research and Development (Grant I-1471- 414.13/2018)
- Boaz Tirosh
Giovanni Armenise-Harvard Foundation (Career Development Award)
- Eelco van Anken
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Hinte et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Repression of viral gene expression and replication by the unfolded protein response effector XBP1u
eLife 9:e51804.
https://doi.org/10.7554/eLife.51804
