Reusch U, Muranyi W, Lucin P, Burgert H G, Hengel H, Koszinowski U H
Max von Pettenkofer-Institut and Genzentrum, Ludwig-Maximilians-Universität München, 81377 München.
EMBO J. 1999 Feb 15;18(4):1081-91. doi: 10.1093/emboj/18.4.1081.
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 beta2-microglobulin (beta2m)-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.
小鼠巨细胞病毒（MCMV）早期基因表达会干扰主要组织相容性复合体I类（MHC I类）抗原呈递途径。在此，我们鉴定出一种由MCMV早期基因m06编码的48 kDa I型跨膜糖蛋白，它在内质网（ER）中与正确折叠的β2-微球蛋白（β2m）相关的MHC I类分子紧密结合。这种结合由该蛋白的腔内/跨膜部分介导。gp48-MHC I类复合物从内质网转运出来，经过高尔基体，但它们不是在细胞表面表达，而是被重新导向内吞途径，并在Lamp-1(+)区室中迅速降解。因此，表达m06的细胞在向CD8(+) T细胞呈递抗原肽方面受损。gp48的细胞质尾巴包含两个双亮氨酸基序。gp48膜近端双亮氨酸基序的突变恢复了MHC I类分子的表面表达，而远端基序的突变则没有影响。这些结果建立了一种新的病毒机制，即通过直接结合靶向表面的MHC复合物并利用细胞双亮氨酸分选机制进行溶酶体降解来下调MHC I类分子。
