A cytomegalovirus glycoprotein re‐routes MHC class I complexes to lysosomes for degradation

Mouse cytomegalovirus (MCMV) early gene expression interferes with the major histocompatibility complex class I (MHC class I) pathway of antigen presentation. Here we identify a 48 kDa type I transmembrane glycoprotein encoded by the MCMV early gene m06, which tightly binds to properly folded β2‐microglobulin (β2m)‐associated MHC class I molecules in the endoplasmic reticulum (ER). This association is mediated by the lumenal/transmembrane part of the protein. gp48–MHC class I complexes are transported out of the 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 presenting antigenic peptides to CD8+ T cells. The cytoplasmic tail of gp48 contains two di‐leucine motifs. Mutation of the membrane‐proximal di‐leucine motif of gp48 restored surface expression of MHC class I, while mutation of the distal one had no effect. The results establish a novel viral mechanism for downregulation of MHC class I molecules by directly binding surface‐destined MHC complexes and exploiting the cellular di‐leucine sorting machinery for lysosomal degradation.

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