Cytomegalovirus Downregulates IRE1 to Repress the Unfolded Protein Response

PLoS Pathogens

Zsolt Ruzsics¹  Albert Sickmann¹  Florian Hinte¹  Julia M. Burkhart²  Boaz Tirosh³  Sebastian Stahl³  Hermine Mohr⁴  Wolfram Brune⁵  René P. Zahedi⁵  Matthias Budt⁶ 

[1] Department of Bioanalytics, ISAS – Leibniz Institute for Analytical Sciences, Dortmund, Germany;Division of Viral Infections, Robert Koch Institute, Berlin, Germany;Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel;Max von Pettenkofer Institute, Ludwig-Maximilians-Universität München, Munich, Germany;Medical Proteome Center (MPC), Ruhr-Universität, Bochum, Germany

关键词: Immunoprecipitation;    Plasmid construction;    Transcription factors;    Endoplasmic reticulum;    Fibroblasts;    Immunoblotting;    Human cytomegalovirus;    Viral replication;   

DOI  :  10.1371/journal.ppat.1003544

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

During viral infection, a massive demand for viral glycoproteins can overwhelm the capacity of the protein folding and quality control machinery, leading to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). To restore ER homeostasis, cells initiate the unfolded protein response (UPR) by activating three ER-to-nucleus signaling pathways, of which the inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved. To reduce ER stress, the UPR decreases protein synthesis, increases degradation of unfolded proteins, and upregulates chaperone expression to enhance protein folding. Cytomegaloviruses, as other viral pathogens, modulate the UPR to their own advantage. However, the molecular mechanisms and the viral proteins responsible for UPR modulation remained to be identified. In this study, we investigated the modulation of IRE1 signaling by murine cytomegalovirus (MCMV) and found that IRE1-mediated mRNA splicing and expression of the X-box binding protein 1 (XBP1) is repressed in infected cells. By affinity purification, we identified the viral M50 protein as an IRE1-interacting protein. M50 expression in transfected or MCMV-infected cells induced a substantial downregulation of IRE1 protein levels. The N-terminal conserved region of M50 was found to be required for interaction with and downregulation of IRE1. Moreover, UL50, the human cytomegalovirus (HCMV) homolog of M50, affected IRE1 in the same way. Thus we concluded that IRE1 downregulation represents a previously undescribed viral strategy to curb the UPR.

【 授权许可】

CC BY