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Journal of Virology, June 2002, p. 5522-5531, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5522-5531.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus K3 Utilizes the Ubiquitin-Proteasome System in Routing Class I Major Histocompatibility Complexes to Late Endocytic Compartments

Mayra E. Lorenzo,1 Jae U. Jung,2 and Hidde L. Ploegh1*

Department of Pathology, Harvard Medical School, Boston Massachusetts 02115,1 Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 017722

Received 26 December 2001/ Accepted 6 March 2002

Human herpesvirus 8 (HHV8) downregulates major histocompatibility complex (MHC) class I complexes from the plasma membrane via two of its genes, K3 and K5. The N termini of K3 and K5 contain a plant homeodomain (PHD) predicted to be structurally similar to RING domains found in E3 ubiquitin ligases. In view of the importance of the ubiquitin-proteasome system in sorting within the endocytic pathway, we analyzed its role in downregulation of MHC class I complexes in cells expressing K3. Proteasome inhibitors as well as cysteine and aspartyl protease inhibitors stabilize MHC class I complexes in cells expressing K3. However, proteasome inhibitors differentially affect sorting of MHC class I complexes within the endocytic pathway and prevent their delivery to a dense endosomal compartment. In this compartment, the cytoplasmic tail of MHC class I complexes is cleaved by cysteine proteases. The complex is then cleaved within the plane of the membrane by an aspartyl protease, resulting in a soluble MHC class I fragment composed of the lumenal domain of the heavy chain, ß2-microglobulin (ß2m), and peptide. We conclude that K3 not only directs internalization, but also targets MHC class I complexes to a dense endocytic compartment on the way to lysosomes in a ubiquitin-proteasome-dependent manner.

* 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 2002, p. 5522-5531, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5522-5531.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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