A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules
A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules
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DOI：
10.1182/blood-2002-07-2158
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发表时间：
2003-04-01
期刊：
影响因子：
20.3
通讯作者：
Ehrlich, R
中科院分区：
文献类型：
--
作者：
Arieh, SVB;Laham, N;Ehrlich, R
HFE 是一种非经典 I 类分子，与 β2 微球蛋白 (β2m) 和转铁蛋白受体结合。 HFE 在含转铁蛋白的内体中积累，其在人类细胞系中的过度表达与转铁蛋白受体 (TFR) 介导的铁吸收减少和细胞内铁池减少相关。干扰 HFE 复合物正确折叠和组装的突变会导致严重的铁过载疾病遗传性血色素沉着症。我们之前提出，病毒也可以通过产生使 HFE 失活的蛋白质来干扰铁代谢，类似于经典类蛋白质。特别是，我们在瞬时表达系统中证明了人巨细胞病毒 (HCMV) US2 靶向 HFE 进行蛋白酶体降解。在这里，我们证明HCMV US2在组成型表达HFE的HEK 293细胞中的稳定表达导致细胞内和细胞表面上HFE表达的丧失，以及经典I类表达的显着减少。 HFE 和经典 I 类分子都通过类似的途径进行降解。 HCMV US2 介导的 HFE 降解导致细胞内铁池增加，如 TfR 合成减少和铁蛋白合成增加所示。这种对铁代谢调节的干扰是否会增强病毒复制和/或促进 HCMV 感染组织的损伤仍有待确定。然而，US2对HFE和经典I类主要组织相容性复合物（MHC）表达的有害影响为HCMV提供了改变细胞代谢功能的有效工具，并支持病毒感染的细胞逃避细胞毒性T淋巴细胞（CTL）介导的免疫反应。
HFE is a nonclassical class I molecule that associates with beta2-microglobulin (beta2m) and with the transferrin receptor. HFE accumulates in transferrin-containing endosomes, and its overexpression in human cell lines correlates with decreased transferrin receptor (TFR)-mediated iron uptake and decreased intracellular iron pools. A mutation that interferes with proper folding and assembly of HFE complexes results in a severe iron-overload disease hereditary hemochromatosis. We previously suggested that viruses could also interfere with iron metabolism through the production of proteins that inactivate HFE, similarly to classical class proteins. In particular, we demonstrated in a transient expression system that human cytomegalovirus (HCMV) US2 targeted HFE for proteasomal degradation. Here we demonstrate that the stable expression of HCMV US2 in HEK 293 cells constitutively expressing HFE leads to loss of HFE expression both intracellularly and on the cell surface, and the significant reduction of classical class I expression. Both HFE and classical class I molecules are targeted to degradation via a similar pathway. This HCMV US2-mediated degradation of HFE leads to increased intracellular iron pools as indicated by reduced synthesis of TfR and increased ferritin synthesis. Whether this interference with regulation of iron metabolism potentiates viral replication and/or promotes damage of HCMV-infected tissues remains to be determined. Nevertheless, the deleterious effect of US2 on the expression of HFE and classical class I major histo-compatibility complexes (MHC) provides HCMV with an efficient tool for altering cellular metabolic functions, as well as supporting the escape of virus-infected cells from cytotoxic T lymphocyte (CTL)-mediated immune responses.