A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation
A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation
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DOI：
10.1093/emboj/18.4.1081
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发表时间：
1999-02-15
期刊：
影响因子：
11.4
通讯作者：
Koszinowski, UH
中科院分区：
文献类型：
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作者：
Reusch, U;Muranyi, W;Koszinowski, UH
小鼠巨细胞病毒（MCMV）早期基因表达干扰抗原呈递的主要组织相容性复合物I类（MHC I类）途径。在此，我们鉴定了MCMV早期基因m06编码的48 kDa I型跨膜糖蛋白，其与内质网（ER）中正确折叠的β（2）-微球蛋白（β（2）m）相关的MHC I类分子紧密结合，这种结合由蛋白质的内腔/跨膜部分介导。gp 48-MHC I类复合物被转运出ER，通过高尔基体，但不是在细胞表面上表达，而是被重定向到内吞途径并在Lamp-1（+）隔室中快速降解。结果，表达m06的细胞在向CD 8（+）T细胞呈递抗原肽方面受损。gp 48的胞质尾部含有两个双亮氨酸基序，gp 48近膜双亮氨酸基序的突变恢复了MHC I类的表面表达，而远端双亮氨酸基序的突变没有影响。这些结果建立了一种新的病毒机制，通过直接结合表面注定的MHC复合物和利用细胞二亮氨酸分选机制进行溶酶体降解来下调MHC I类分子。
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 beta(2)-microglobulin (beta(2)m)-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 down-regulation of MHC class I molecules by directly binding surface-destined MHC complexes and exploiting the cellular di-leucine sorting machinery for lysosomal degradation.