Repression of viral gene expression and replication by the unfolded protein response effector XBP1U

Florian Hinte, Eelco Van Anken, Boaz Tirosh, Wolfram Brune*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageAmerican English
Article numbere51804
JournaleLife
Volume9
DOIs
StatePublished - Feb 2020

Bibliographical note

Funding Information:
We thank D. Thomas Rutkowski for providing Atf6-/- MEFs and Svenja Siebels for helpful advice on the DPI-ELISA. This study was supported by the Deutsche Forschungsgemeinschaft (BR 1730/6-1 to WB), the EU Horizon 2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant 721236 to BT), the German-Israeli Foundation (Grant I-1471-414.13/2018 to BT), and Giovanni Armenise-Harvard Foundation (Career Development Award to EvA).

Funding Information:
We thank D. Thomas Rutkowski for providing Atf6 MEFs and Svenja Siebels for helpful advice on the DPI-ELISA. This study was supported by the Deutsche Forschungsgemeinschaft (BR 1730/6-1 to WB), the EU Horizon 2020 Marie SklodowskaCurie ITN-TREATMENT (Grant 721236 to BT), the German-Israeli Foundation (Grant I-1471-414.13/2018 to BT), and Giovanni Armenise-Harvard Foundation (Career Development Award to EvA).

Publisher Copyright:
© 2020, eLife Sciences Publications Ltd. All rights reserved.

Keywords

  • Unfolded protein response/transcription factor/XBP1u/ATF6/cytomegalovirus

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