Dengue virus serotype infection specifies the activation of the unfolded protein response.
BACKGROUND
Dengue and Dengue hemorrhagic fever have emerged as some of the most important mosquito-borne viral diseases in the tropics. The mechanisms of pathogenesis of Dengue remain elusive. Recently, virus-induced apoptosis mediated by the Unfolded Protein Response (UPR) has been hypothesised to represent a crucial pathogenic event in viral infection. In an attempt to evaluate the contribution of the UPR to virus replication, we have characterized each component of this signalling pathway following Dengue virus infection.


RESULTS
We find that upon Dengue virus infection, A549 cells elicit an UPR which is observed at the level of translation attenuation (as visualized by the phosphorylation of eIF2alpha) and activation of specific pathways such as nuclear translocation of ATF-6 and splicing of XBP-1. Interestingly, we find that specific serotype of virus modulate the UPR with different selectivity. In addition, we demonstrate that perturbation of the UPR by preventing the dephosphorylation of the translation initiation factor eIF2alpha using Salubrinal considerably alters virus infectivity.


CONCLUSIONS
This report provides evidence that Dengue infection induces and regulates the three branches of the UPR signaling cascades. This is a basis for our understanding of the viral regulation and conditions beneficial to the viral infection. Furthermore, modulators of UPR such as Salubrinal that inhibit Dengue replication may open up an avenue toward cell-protective agents that target the endoplasmic reticulum for anti-viral therapy.
Umareddy
Indira
I
Novartis Institute for Tropical Diseases, 10-Biopolis Road, #05-01 Chromos, 138670, Singapore. indira.umareddy@gmail.com
Pluquet
Olivier
O
Wang
Qing Yin
QY
Vasudevan
Subhash G
SG
Chevet
Eric
E
Gu
Feng
F
D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003716:Dengue Virus / Q000472:pathogenicity* / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017510:Protein Folding; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D019595:Severe Dengue / Q000378:metabolism / Q000821:virology; D014157:Transcription Factors; D014779:Virus Replication; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1