PERK Is Critical for Alphavirus Nonstructural Protein Translation
Abstract
Venezuelan equine encephalitis virus (VEEV) is an alphavirus that causes encephalitis. Previous work indicated that VEEV infection induced early growth response 1 (EGR1) expression, leading to cell death via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the unfolded protein response (UPR) pathway. Loss of PERK prevented EGR1 induction and decreased VEEV-induced death. The results presented within show that loss of PERK in human primary astrocytes dramatically reduced VEEV and eastern equine encephalitis virus (EEEV) infectious titers by 4–5 log10. Loss of PERK also suppressed VEEV replication in primary human pericytes and human umbilical vein endothelial cells, but it had no impact on VEEV replication in transformed U87MG and 293T cells. A significant reduction in VEEV RNA levels was observed as early as 3 h post-infection, but viral entry assays indicated that the loss of PERK minimally impacted VEEV entry. In contrast, the loss of PERK resulted in a dramatic reduction in viral nonstructural protein translation and negative-strand viral RNA production. The loss of PERK also reduced the production of Rift Valley fever virus and Zika virus infectious titers. These data indicate that PERK is an essential factor for the translation of alphavirus nonstructural proteins and impacts multiple RNA viruses, making it an exciting target for antiviral development.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 12, 2021
- Source ID
- 10.3390/v13050892
Entities
People
- Bibha Dahal
- Caitlin Lehman
- Ivan Akhrymuk
- Jonathan D. Dinman
- Jonathan Jacobs
- Kylene Kehn-Hall
- Lauren Panny
- Michael D. Barrera
- Nicole Bracci
- Nishank Bhalla
Organizations
- Defense Threat Reduction Agency