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, ␤ 2 -microglobulin (␤ 2 m), 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.Antigen presentation via the major histocompatibility complex (MHC) class I pathway is targeted for interference at different stages by several viruses (26,46). Virtually every herpesvirus studied encodes at least one gene product that negatively affects MHC class I expression in the infected cell. Human herpesvirus 8 (HHV8), a gamma-2 herpesvirus, also known as Kaposi's sarcoma-associated herpesvirus (KSHV), downregulates expression of MHC class I complexes at the cell surface via two gene products, K3 and K5 (7, 22). Both genes independently induce internalization of MHC class I complexes from the plasma membrane, which ultimately results in lysosomal degradation of MHC class I complexes. The specificity of K3 and K5 differs for different MHC class I alleles and depends on the transmembrane domain of the class I molecule. K3 induces internalization of HLA-A, -B, -C, and -E, while K5 induces internalization of HLA-A and -B and only a small fraction of HLA-E. In addition, K5 downregulates B7-2 and ICAM-1 (8, 21).K3 shares 40% amino acid identity with K5 (30). Both genes contain in their N terminus a variant of the C 4 HC 3 zinc finger domain class, termed the plant homeodomain (PHD)/leukemia-associated protein (LAP) motif. It has been shown recently that an intact PHD is required for MHC class I downregulation by K3 (28). While PHDs (for review, see reference 1) are similar to RING fingers and LIM (Lin11/Isl-1/Mec3) domains, their function remains unknown. Structural analysis by nuclear magnetic resonance of the PHD in the transcriptional corepressor KAP-1 shows its structural similarity with the prototype C 3 HC 4 pattern RING fingers (6). Nicholas et al. (39) have categorized the PHDs of K3 and K5 as the BKS (bovine her...

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