Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome
Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome
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DOI：
10.1073/pnas.94.5.1896
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发表时间：
1997-03-04
影响因子：
11.1
通讯作者：
Cresswell, P
中科院分区：
文献类型：
--
作者：
Hughes, EA;Hammond, C;Cresswell, P
N-乙酰基-L-亮氨酰-L-亮氨酰-L-正亮氨酸（LLnL），可逆抑制蛋白酶体以及其他蛋白酶，以及蛋白酶体的更特异性不可逆抑制剂lactacystin，被发现导致主要组织相容性复合体（MHC）I类重链在β（2）-微球蛋白缺陷细胞系Daudi和TAP缺陷细胞系的胞质溶胶中积累。这些细胞系折叠MHC I类重链的能力严重受损，在LLnL存在下，在数小时内显示出可溶性I类重链以不同速率的积累，在LLnL或乳胞素存在下可溶性I类重链的积累在Daudi和.174中很容易揭示，但在表达β（2）-半胱氨酸蛋白酶抑制剂的Daudi转染子中几乎检测不到。还发现可溶性I类重链缺乏其N-连接的聚糖并且位于胞质溶胶中。当将ICP 47（一种阻断肽易位到内质网中的单纯疱疹病毒蛋白）的基因转染到45.1中时，可检测到可溶性MHC I类重链的类似积累。这些数据表明，在MHC I类分子不能正确组装的细胞中，错误折叠的重链从内质网移到胞质溶胶中，去糖基化，并被蛋白酶体降解。
N-acetyl-L-leucyl-L-leucyl-L-norleucinal (LLnL), which reversibly inhibits the proteasome in addition to other proteases, and a more specific irreversible inhibitor of the proteasome, lactacystin, were found to cause the accumulation of major histocompatibility complex (MHC) class I heavy chains in the cytosol of the beta(2)-microglobulin-deficient cell line Daudi and the TAP-deficient cell line .174. These cell lines, which are severely impaired in their ability to fold MHC class I heavy chain, showed an accumulation of soluble class I heavy chains at different rates over a period of hours in the presence of LLnL, The accumulation of soluble class I heavy chains in the presence of either LLnL or lactacystin was easily revealed in Daudi and .174 but almost undetectable in a Daudi transfectant expressing beta(2)-microglobulin and in 45.1, the wild-type parent of .174, The soluble class I heavy chain was also found to be devoid of its N-linked glycan and to be located in the cytosol, When the gene for ICP47, a herpes simplex virus protein that blocks the translocation of peptides into the endoplasmic reticulum, was transfected into 45.1, a similar accumulation of soluble MHC class I heavy chain was detectable, These data suggest that in cells where the MHC class I molecule is unable to assemble properly, the misfolded heavy chain is removed from the endoplasmic reticulum to the cytosol, deglycosylated, and degraded by the proteasome.