Affiliation:
1. Graduate Institute of Life Sciences
2. Institute of Biomedical Sciences
3. Department of Microbiology and Immunology, National Defense Medical Center
4. Genomics Research Center, Academia Sinica, Taipei, Taiwan, Republic of China
Abstract
ABSTRACT
The unfolded protein response (UPR) is a coordinated change in gene expression triggered by perturbations in functions of the endoplasmic reticulum (ER). XBP1, a key transcription factor of the UPR, is activated by an IRE1-mediated splicing event, which results in a frameshift and encodes a protein with transcriptional activity. Here, we report that XBP1 was activated during flaviviral infection, as evidenced by
XBP1
mRNA splicing and protein expression, as well as induction of the downstream genes
ERdj4
,
EDEM1
, and
p58(IPK)
in Japanese encephalitis virus (JEV)- and dengue virus serotype 2 (DEN-2)-infected cells. Reporter systems based on IRE1-mediated
XBP1
splicing were established, and several flaviviral proteins associated with the ER, including glycoproteins and small hydrophobic membrane-anchored proteins, were found to trigger the splicing event. Notably, nonstructural protein NS2B-3 of DEN-2, but not of JEV, was a potent inducer of
XBP1
splicing through an unclear mechanism(s). Reduction of XBP1 by a small interfering RNA had no effect on cells' susceptibility to the two viruses but exacerbated the flavivirus-induced cytopathic effects. Overall, flaviviruses trigger the XBP1 signaling pathway and take advantage of this cellular response to alleviate virus-induced cytotoxicity.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology