Abstract
ABSTRACTAs obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with dengue virus (DENV) and Zika virus (ZIKV), two positive-strand RNA flaviviruses. Polysome profiling and analysis of de novo protein synthesis revealed that flavivirus infection causes potent repression of host cell translation, while synthesis of viral proteins remains efficient. Selective repression of host cell translation was mediated by the DENV polyprotein at the level of translation initiation. In addition, DENV and ZIKV infection suppressed host cell stress responses such as the formation of stress granules and phosphorylation of the translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2). Mechanistic analyses revealed that translation repression was uncoupled from the disruption of stress granule formation and eIF2α signaling. Rather, DENV infection induced p38-Mnk1 signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles. Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells.
Highlights
As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells synthesize antiviral proteins to limit virus infection
dengue virus (DENV) infections were carried out with the serotype 2 strain New Guinea C (NGC) at a high multiplicity of infection (MOI) of 10 50% tissue culture infective doses (TCID50) per cell, unless otherwise stated, to synchronize the infection kinetics and reduce the effects resulting from viral spread
Since translation suppression in DENV-infected cells did not result from eIF2␣ inactivation, we explored whether DENV infection impairs alternative regulators of translation initiation: e.g., the ability to assemble the cap-eIF4F complex [66]
Summary
Viruses strictly depend on host cell translation for the production of new progeny, yet infected cells synthesize antiviral proteins to limit virus infection. DENV infection induced p38-Mnk signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells. Inhibition of protein synthesis is tightly linked to the assembly of stress granules (SGs), which are cytosolic aggregates of stalled translation preinitiation complexes [5,6,7] As they require an intact translation machinery to translate their viral genome, several viruses antagonize SG formation during infection, some may exploit SG responses for their replication [8, 9]. Viral RNA is replicated through dsRNA intermediates likely shielded in virus-induced rearrangements of the endoplasmic reticulum membranes called vesicle packets [29, 30]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call