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Journal of Virology, June 2001, p. 5197-5204, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5197-5204.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Cytomegalovirus US2 Endoplasmic Reticulum-Lumenal Domain Dictates Association with Major Histocompatibility Complex Class I in a Locus-Specific Manner

Benjamin E. Gewurz,1 Evelyn W. Wang,1 Domenico Tortorella,1 Danny J. Schust,2 and Hidde L. Ploegh1,*

Department of Pathology1 and The Fearing Laboratory and The Division of Reproductive Endocrinology and Fertility, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital,2 Harvard Medical School, Boston, Massachusetts 02115

Received 24 January 2001/Accepted 12 March 2001

The human cytomegalovirus-encoded US2 glycoprotein targets endoplasmic reticulum-resident major histocompatibility complex (MHC) class I heavy chains for rapid degradation by the proteasome. We demonstrate that the endoplasmic reticulum-lumenal domain of US2 allows tight interaction with class I molecules encoded by the HLA-A locus. Recombinant soluble US2 binds properly folded, peptide-containing recombinant HLA-A2 molecules in a peptide sequence-independent manner, consistent with US2's ability to broadly downregulate class I molecules. The physicochemical properties of the US2/MHC class I complex suggest a 1:1 stoichiometry. These results demonstrate that US2 does not require additional cellular proteins to specifically interact with soluble class I molecules. Binding of US2 does not significantly alter the conformation of class I molecules, as a soluble T-cell receptor can simultaneously recognize class I molecules associated with US2. The lumenal domain of US2 can differentiate between the products of distinct class I loci, as US2 binds several HLA-A locus products while being unable to bind recombinant HLA-B7, HLA-B27, HLA-Cw4, or HLA-E. We did not observe interaction between soluble US2 and either recombinant HLA-DR1 or recombinant HLA-DM. The substrate specificity of US2 may help explain the presence in human cytomegalovirus of multiple strategies for downregulation of MHC class I molecules.

* Corresponding author. Mailing address: Department of Pathology, Harvard Medical School, Building D2, Room 137, 200 Longwood Ave., Boston, MA 02115. Phone: (617) 432-4776. Fax: (617) 432-4775. E-mail: ploegh{at}hms.harvard.edu.

Journal of Virology, June 2001, p. 5197-5204, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5197-5204.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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