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Journal of Virology, December 2006, p. 11868-11880, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00879-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress{triangledown}

Chia-Yi Yu,1,2 Yun-Wei Hsu,2,3 Ching-Len Liao,1,3 and Yi-Ling Lin1,2,4*

Graduate Institute of Life Sciences,1 Department of Microbiology and Immunology, National Defense Medical Center,3 Institute of Biomedical Sciences,2 Genomics Research Center, Academia Sinica, Taipei, Taiwan, Republic of China4

Received 1 May 2006/ Accepted 6 September 2006

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.

* Corresponding author. Mailing address: Institute of Biomedical Sciences, Academia Sinica, No. 128, Sec. 2, Academy Road, Taipei 115, Taiwan, Republic of China. Phone: (886) 2-2652-3902. Fax: (886) 2-2785-8847. E-mail: yll{at}ibms.sinica.edu.tw.

{triangledown} Published ahead of print on 20 September 2006.

Journal of Virology, December 2006, p. 11868-11880, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00879-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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