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Journal of Virology, March 2005, p. 2768-2779, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2768-2779.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Protein US11 Provokes an Unfolded Protein Response That May Facilitate the Degradation of Class I Major Histocompatibility Complex Products

Boaz Tirosh,1 Neal N. Iwakoshi,2 Brendan N. Lilley,1 Ann-Hwee Lee,2 Laurie H. Glimcher,2 and Hidde L. Ploegh1*

Department of Pathology, Harvard Medical School,1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts2

Received 26 June 2004/ Accepted 12 October 2004

The human cytomegalovirus (HCMV) glycoprotein US11 diverts class I major histocompatibility complex (MHC) heavy chains (HC) from the endoplasmic reticulum (ER) to the cytosol, where HC are subjected to proteasome-mediated degradation. In mouse embryonic fibroblasts that are deficient for X-box binding protein 1 (XBP-1), a key transcription factor in the unfolded protein response (UPR) pathway, we show that degradation of endogenous mouse HC is impaired. Moreover, the rate of US11-mediated degradation of ectopically expressed HLA-A2 is reduced when XBP-1 is absent. In the human astrocytoma cell line U373, turning on expression of US11, but not US2, is sufficient to induce a UPR, as manifested by upregulation of the ER chaperone Bip and by splicing of XBP-1 mRNA. In the presence of dominant-negative versions of XBP-1 and activating transcription factor 6, the kinetics of class I MHC HC degradation were delayed when expression of US11 was turned on. The magnitude of these effects, while reproducible, was modest. Conversely, in cells that stably express high levels of US11, the degradation of HC is not affected by the presence of the dominant negative effectors of the UPR. An infection of human foreskin fibroblasts with human cytomegalovirus induced XBP-1 splicing in a manner that coincides with US11 expression. We conclude that the contribution of the UPR is more pronounced on HC degradation shortly after induction of US11 expression and that US11 is sufficient to induce such a response.

* Corresponding author. Mailing address: Department of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Room 836, Boston MA 02115. Phone: (617) 432-4777. Fax: (617) 432-4775. E-mail: hidde_ploegh{at}hms.harvard.edu.

Journal of Virology, March 2005, p. 2768-2779, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2768-2779.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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