Repression of viral gene expression and replication by the unfolded protein response effector XBP1u

  1. Florian Hinte
  2. Eelco van Anken
  3. Boaz Tirosh
  4. Wolfram Brune  Is a corresponding author
  1. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Germany
  2. San Raffaele Scientific Institute, Italy
  3. 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

  1. Florian Hinte

    Virus-Host Interactions, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
    Competing interests
    No competing interests declared.
  2. Eelco van Anken

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    Eelco van Anken, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9529-2701
  3. Boaz Tirosh

    School of Pharmacy, Institute for Drug Research, Jerusalem, Israel
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8067-6577
  4. Wolfram Brune

    Virus-Host Interactions, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
    For correspondence
    wolfram.brune@leibniz-hpi.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6078-5255

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.

Reviewing Editor

  1. Karla Kirkegaard, Stanford University School of Medicine, United States

Publication history

  1. Received: September 11, 2019
  2. Accepted: February 17, 2020
  3. Accepted Manuscript published: February 17, 2020 (version 1)
  4. Version of Record published: March 19, 2020 (version 2)

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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  1. Florian Hinte
  2. Eelco van Anken
  3. Boaz Tirosh
  4. Wolfram Brune
(2020)
Repression of viral gene expression and replication by the unfolded protein response effector XBP1u
eLife 9:e51804.
https://doi.org/10.7554/eLife.51804

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