TUMOR REJECTION ANTIGEN GP96/GRP94 IS AN ATPASE - IMPLICATIONS FOR PROTEIN-FOLDING AND ANTIGEN PRESENTATION
TUMOR REJECTION ANTIGEN GP96/GRP94 IS AN ATPASE - IMPLICATIONS FOR PROTEIN-FOLDING AND ANTIGEN PRESENTATION
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DOI：
10.1002/j.1460-2075.1993.tb05983.x
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发表时间：
1993-08-01
期刊：
影响因子：
11.4
通讯作者：
SRIVASTAVA, PK
中科院分区：
文献类型：
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作者：
LI, ZH;SRIVASTAVA, PK
用 gp96/grp94 热休克蛋白 (HSP) 免疫小鼠可引发针对分离出 gp96 的肿瘤的肿瘤特异性细胞免疫。然而，gp96 的 cDNA 序列在肿瘤和正常组织中是相同的。这就提出了关于 gp96 特异性免疫原性的结构基础的问题。由于 HSP 结合包括肽在内的多种分子，我们提出 gp96 本身可能不具有免疫原性，但可能陪伴抗原肽。此外，gp96 主要定位于内质网 (ER) 的腔中，表明它可能充当肽受体并作为 MHC I 类分子的肽负载的辅助物。我们在此证明 gp96 分子含有 ATP 结合盒、结合 ATP 并具有 Mg2+ 依赖性 ATP 酶活性。还观察到 Gp96 制剂含有紧密结合的肽，可以通过酸提取将其洗脱。 gp96 的这些特性与其在陪伴抗原肽和促进 ER 腔中 MHC I 类肽组装中的拟议作用一致。我们提出了一个模型来解释 gp96 与 MHC I 类的相互作用如何导致肽转移到后者。
Immunization of mice with gp96/grp94 heat shock proteins (HSPs) elicits tumor-specific cellular immunity to the tumors from which gp96 is isolated. However, the cDNA sequence of gp96 is identical among tumors and normal tissues. This raises the question regarding the structural basis of the specific immunogenicity of gp96. As HSPs bind a wide array of molecules including peptides, we have proposed that gp96 may not be immunogenic per se, but may chaperone antigenic peptides. Furthermore, gp96 is localized predominantly in the lumen of the endoplasmic reticulum (ER) suggesting that it may act as a peptide acceptor and as accessory to peptide loading of MHC class I molecules. We demonstrate here that gp96 molecules contain ATP-binding cassettes, bind ATP and possess an Mg2+-dependent ATPase activity. Gp96 preparations are also observed to contain tightly bound peptides, which can be eluted by acid extraction. These properties of gp96 are consistent with its proposed roles in chaperoning antigenic peptides and in facilitating MHC class I-peptide assembly in the ER lumen. We present a model to explain how interaction of gp96 with MHC class I may result in transfer of peptides to the latter.