Inositol-requiring enzyme 1 inhibits respiratory syncytial virus replication.
Despite being a major health problem, respiratory syncytial virus (RSV) infections remain without specific therapy. Identification of novel host cellular responses that play a role in the pathogenesis of RSV infection is needed for therapeutic development. The endoplasmic reticulum (ER) stress response is an evolutionarily conserved cellular signaling cascade that has been implicated in multiple biological phenomena, including the pathogenesis of some viral infections. In this study, we investigate the role of the ER stress response in RSV infection using an in vitro A549 cell culture model. We found that RSV infection induces a non-canonical ER stress response with preferential activation of the inositol-requiring enzyme 1 (IRE1) and activated transcription factor 6 (ATF6) pathways with no concomitant significant activation of the protein kinase R-like ER kinase (PERK) pathway. Furthermore, we discovered that IRE1 has an inhibitory effect on RSV replication. Our data characterize, for the first time, the nature of the ER stress response in the setting of RSV infection and identify the IRE1 stress pathway as a novel cellular anti-RSV defense mechanism.
From the Department of Internal Medicine, Carver College of Medicine and.
Ihab
I
Hassan
Kayla S
KS
Gaines
Wesley J
WJ
Hottel
Ryan M
RM
Wishy
Sara E
SE
Miller
Linda S
LS
Powers
D Thomas
DT
Rutkowski
Martha M
MM
Monick
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012326:RNA Splicing; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism*; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D015398:Signal Transduction; D014779:Virus Replication
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C528229:ERN1 protein, human; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
Cell Biology; Cell Signaling; ER Stress; IRE1; Negative-strand RNA Viruses; Viral Replication