Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules.
Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules.
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DOI：
10.1099/vir.0.83516-0
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发表时间：
2008-05
期刊：
影响因子：
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通讯作者：
Kristina Oresić;D. Tortorella
中科院分区：
文献类型：
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作者：
Kristina Oresić;D. Tortorella
人巨细胞病毒（HCMV，一种β-疱疹病毒）抑制主要组织相容性复合物I类分子的细胞表面表达，促进逃避CD 8+细胞毒性T细胞的识别。HCMV US 2和US 11基因产物通过促进I类重链的降解在HCMV感染的早期诱导I类下调。HCMV蛋白通过称为“移位”的过程促进I类重链穿过内质网（ER）膜转运到胞质溶胶中，然后进行蛋白酶体降解。这一过程与ER质量控制介导的错误折叠ER蛋白的降解具有惊人的相似性。即使错位反应的主要步骤已被表征，但细胞蛋白，特别是参与靶向I类错位的ER分子伴侣，尚未被完全描述。为了阐明参与HCMV介导的I类脱位的分子伴侣，我们利用了在其羧基末端具有亲和标签的嵌合I类重链。有趣的是，US 2而不是US 11继续靶向I类嵌合体进行破坏，这表明US 11介导的降解存在结构限制。在US 2细胞和表达US 2突变体US 2 - 186 HA的细胞中的关联研究揭示，I类特异性地与钙连接蛋白、BiP和钙网蛋白相互作用。这些研究结果表明，US 2介导的I类破坏利用特定的分子伴侣，以促进I类脱位。这些数据表明一个更一般的模型，其中介导蛋白质折叠的分子伴侣也可能在ER质量控制过程中起作用，以消除异常的ER蛋白。
Inhibition of cell-surface expression of major histocompatibility complex class I molecules by human cytomegalovirus (HCMV, a beta-herpesvirus) promotes escape from recognition by CD8+ cytotoxic T cells. The HCMV US2 and US11 gene products induce class I downregulation during the early phase of HCMV infection by facilitating the degradation of class I heavy chains. The HCMV proteins promote the transport of the class I heavy chains across the endoplasmic reticulum (ER) membrane into the cytosol by a process referred to as 'dislocation', which is then followed by proteasome degradation. This process has striking similarities to the degradation of misfolded ER proteins mediated by ER quality control. Even though the major steps of the dislocation reaction have been characterized, the cellular proteins, specifically the ER chaperones involved in targeting class I for dislocation, have not been fully delineated. To elucidate the chaperones involved in HCMV-mediated class I dislocation, we utilized a chimeric class I heavy chain with an affinity tag at its carboxy terminus. Interestingly, US2 but not US11 continued to target the class I chimera for destruction, suggesting a structural limitation for US11-mediated degradation. Association studies in US2 cells and in cells that express a US2 mutant, US2-186HA, revealed that class I specifically interacts with calnexin, BiP and calreticulin. These findings demonstrate that US2-mediated class I destruction utilizes specific chaperones to facilitate class I dislocation. The data suggest a more general model in which the chaperones that mediate protein folding may also function during ER quality control to eliminate aberrant ER proteins.