Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation.
The Kaposi's sarcoma-associated herpes virus gene product K3 (KK3) subverts the MHC class I antigen presentation pathway by downregulating MHC class I from the plasma membrane. We now show that KK3 associates with MHC class I molecules and promotes ubiquitylation of class I after export from the endoplasmic reticulum. Ubiquitylation requires the KK3 N-terminal plant homeodomain and provides the signal for class I internalization at the plasma membrane. Once internalized, ubiquitylated MHC class I is targeted to the late endocytic pathway, where it is degraded. Depletion by small interfering RNA of TSG101, a ubiquitin enzyme 2 variant protein involved in late endosomal sorting, prevents class I degradation and preserves cell surface class I expression in KK3-expressing cells. These results suggest a mechanism by which the KK3-induced class I ubiquitylation provides a signal for both internalization and sorting to the late endosomal pathway for degradation. KK3 is the first viral gene product that subverts the trafficking of a host protein via the ubiquitin-dependent endosomal sorting machinery.
Hewitt
Eric W
EW
Department of Pathology, Division of Immunology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Duncan
Lidia
L
Mufti
Dina
D
Baker
John
J
Stevenson
Philip G
PG
Lehner
Paul J
PJ
D004268:DNA-Binding Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D016350:Leucine Zippers; D016366:Open Reading Frames; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D016335:Zinc Fingers; D000099177:Tsg101 Protein
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015395:Histocompatibility Antigens Class I; D011994:Recombinant Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D014764:Viral Proteins; D000099177:Tsg101 Protein; C456022:K3 protein, Kaposi's sarcoma-associated herpesvirus