期刊
JOURNAL OF VIROLOGY
卷 76, 期 11, 页码 5522-5531出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.76.11.5522-5531.2002
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资金
- NCI NIH HHS [R01 CA091819, CA91819] Funding Source: Medline
- NIAID NIH HHS [P01 AI042257, P01 AI42257] Funding Source: Medline
- NIGMS NIH HHS [F31 GM18258, F31 GM018258] Funding Source: Medline
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, beta(2)-microglobulin (beta(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.
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