Abstract
A virus that reproduces in a host without killing cells can easily establish a successful infection. Previously, we showed that dengue-2, a virus that threatens 40% of the world, induces autophagy, enabling dengue to reproduce in cells without triggering cell death. Autophagy further protects the virus-laden cells from further insults. In this study, we evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS). Inhibition of ER stress or ATM signaling abrogates the dengue-conferred protection against other cell stressors. Direct inhibition of ER stress response in infected cells decreases autophagosome turnover, reduces ROS production and limits reproduction of dengue virus. Blocking ATM activation, which is an early response to infection, decreases transcription of ER stress response proteins, but ATM has limited impact on production of ROS and virus titers. Production of ROS determines only late-onset autophagy in infected cells and is not necessary for dengue-induced protection from stressors. Collectively, these results demonstrate that among the multiple autophagy-inducing pathways during infection, ER stress signaling is more important to viral replication and protection of cells than either ATM or ROS-mediated signaling. To limit virus production and survival of dengue-infected cells, one must address the earliest phase of autophagy, induced by ER stress.
Highlights
These viruses regulate the metabolism and survival of infected cells, assuring their own reproduction and propagation
Autophagy further protects the virus-laden cells from further insults. We evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS)
Using specific primers for quantitative PCR (qPCR), we found that salubrinal decreased transcription of the viral NS4A gene by 440% (Figure 1d), indicating the importance of PERK signaling in virus replication and transcription
Summary
These viruses regulate the metabolism and survival of infected cells, assuring their own reproduction and propagation. Monocyte chemotactic protein-1 (MCP-1), known to mediate cardiac injury, induces ROS, ER stress and autophagy in cardiac myoblasts (H9c2 cells).[19] In most cases, as in mouse disease models, induction of autophagy by ER stress serves as a protective mechanism against apoptotic cell death.[20] One of the most important branches of ER stress/unfolded protein response (UPR) signaling – eukaryotic translation initiation factor-2α (eIF2α/protein kinase R-like endoplasmic reticulum kinase (PERK)) – is activated in response to accumulation of proteins with polyglutamine repeats and functions in LC3 lipidation and autophagosome formation.[21] PERK-induced autophagy protects mouse and human lymphomas during pathogenic conditions (Myc-induced tumorigenesis).[22] Downstream ER stress components like C/EBP homologous protein (CHOP), a PERK-regulated protein, and inositol-requiring protein 1 (IRE1) increase autophagy in colon cancer cell lines like HT29 (human colon adenocarcinoma cell line), SW480 (human colorectal adenocarcinoma cell line) and Caco-2,23 demonstrating the involvement of ER stress signaling in the induction of autophagy
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