Mouse cytomegalovirus (MCMV) early gene expression interferes with the majo
r histocompatibility complex class I (MHC class I) pathway of antigen prese
ntation. Here we identify a 48 kDa type I transmembrane glycoprotein encode
d by the MCMV early gene m06, which tightly binds to properly folded beta(2
)-microglobulin (beta(2)m)-associated MHC class I molecules in the endoplas
mic reticulum (ER), This association is mediated by the lumenal/transmembra
ne part of the protein. gp48-MHC class I complexes are transported out of t
he ER, pass the Golgi, but instead of being expressed on the cell surface,
they are redirected to the endocytic route and rapidly degraded in a Lamp-1
(+) compartment, As a result, m06-expressing cells are impaired in presenti
ng antigenic peptides to CD8(+) T cells. The cytoplasmic tail of gp48 conta
ins two di-leucine motifs, Mutation of the membrane-proximal di-leucine mot
if of gp48 restored surface expression of MHC class I, while mutation of th
e distal one had no effect. The results establish a novel viral mechanism f
or down-regulation of MHC class I molecules by directly binding surface-des
tined MHC complexes and exploiting the cellular di-leucine sorting machiner
y for lysosomal degradation.