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Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101‐dependent degradation
Author(s) -
Hewitt Eric W.,
Duncan Lidia,
Mufti Dina,
Baker John,
Stevenson Philip G.,
Lehner Paul J.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.10.2418
Subject(s) - biology , internalization , ubiquitin , mhc class i , tsg101 , microbiology and biotechnology , immunoprecipitation , protein degradation , virology , major histocompatibility complex , biochemistry , genetics , antibody , immune system , cell , gene , microrna , microvesicles
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.