Dengue virus selectively annexes endoplasmic reticulum-associated translation machinery as a strategy for co-opting host cell protein synthesis

David W. Reid, Rafael K. Campos, Jessica R. Child, Tianli Zheng, Kitti Wing Ki Chan, Shelton Bradrick, Subhash G. Vasudevan, Mariano Garcia-Blanco, Christopher V. Nicchitta

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

A primary question in dengue virus (DENV) biology is the molecular strategy for recruitment of host cell protein synthesis machinery. Here, we combined cell fractionation, ribosome profiling, and transcriptome sequencing (RNA-seq) to investigate the subcellular organization of viral genome translation and replication as well as host cell translation and its response to DENV infection. We report that throughout the viral life cycle, DENV plus- and minus-strand RNAs were highly partitioned to the endoplasmic reticulum (ER), identifying the ER as the primary site of DENV translation. DENV infection was accompanied by an ER compartment-specific remodeling of translation, where ER translation capacity was subverted from host transcripts to DENV plus-strand RNA, particularly at late stages of infection. Remarkably, translation levels and patterns in the cytosol compartment were only modestly affected throughout the experimental time course of infection. Comparisons of ribosome footprinting densities of the DENV plus-strand RNA and host mRNAs indicated that DENV plus-strand RNA was only sparsely loaded with ribosomes. Combined, these observations suggest a mechanism where ER-localized translation and translational control mechanisms, likely cis encoded, are used to repurpose the ER for DENV virion production. Consistent with this view, we found ER-linked cellular stress response pathways commonly associated with viral infection, namely, the interferon response and unfolded protein response, to be only modestly activated during DENV infection. These data support a model where DENV reprograms the ER protein synthesis and processing environment to promote viral survival and replication while minimizing the activation of antiviral and proteostatic stress response pathways.

Original languageEnglish (US)
Article numbere01766-17
JournalJournal of Virology
Volume92
Issue number7
DOIs
StatePublished - Apr 1 2018

Fingerprint

Dengue virus
Dengue Virus
Endoplasmic Reticulum
endoplasmic reticulum
translation (genetics)
protein synthesis
Proteins
Virus Diseases
cells
RNA
ribosomes
Ribosomes
infection
stress response
cell fractionation
unfolded protein response
RNA Sequence Analysis
Cell Fractionation
Unfolded Protein Response
Viral Genome

Keywords

  • Flavivirus
  • Organelle protein import
  • RNA virus
  • Translational control

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Dengue virus selectively annexes endoplasmic reticulum-associated translation machinery as a strategy for co-opting host cell protein synthesis. / Reid, David W.; Campos, Rafael K.; Child, Jessica R.; Zheng, Tianli; Chan, Kitti Wing Ki; Bradrick, Shelton; Vasudevan, Subhash G.; Garcia-Blanco, Mariano; Nicchitta, Christopher V.

In: Journal of Virology, Vol. 92, No. 7, e01766-17, 01.04.2018.

Research output: Contribution to journalArticle

Reid, David W. ; Campos, Rafael K. ; Child, Jessica R. ; Zheng, Tianli ; Chan, Kitti Wing Ki ; Bradrick, Shelton ; Vasudevan, Subhash G. ; Garcia-Blanco, Mariano ; Nicchitta, Christopher V. / Dengue virus selectively annexes endoplasmic reticulum-associated translation machinery as a strategy for co-opting host cell protein synthesis. In: Journal of Virology. 2018 ; Vol. 92, No. 7.
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