Peaper David R, Cresswell Peter
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8011, USA.
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10477-82. doi: 10.1073/pnas.0805044105. Epub 2008 Jul 23.
ERp57 is an oxidoreductase that, in conjunction with calnexin and calreticulin, assists disulfide bond formation in folding glycoproteins. ERp57 also forms a mixed disulfide with the MHC class I-specific chaperone tapasin, and this dimeric conjugate edits the peptide repertoire bound by MHC class I molecules. In cells unable to form the conjugate, because of tapasin mutation in human studies or ERp57 deletion in mouse studies, peptide loading is impeded. Subtle differences between the mouse and human systems have been observed. Here, we address these differences and expand the analysis to investigate the role of ERp57 redox functions in MHC class I peptide loading. We show in human cells that in the absence of conjugate formation MHC class I recruitment and/or stabilization in the MHC class I peptide-loading complex is impaired, similar to observations in mouse cells. However, we found no role for the enzymatic activities of either the a or a' domain redox sites of ERp57 in peptide loading. Our data argue that the function of ERp57 in peptide loading is likely caused by other ERp57 functional domains or a combinatorial feature of the tapasin-ERp57 conjugate.
ERp57是一种氧化还原酶，它与钙连蛋白和钙网蛋白协同作用，在折叠糖蛋白过程中协助二硫键的形成。ERp57还与MHC I类特异性伴侣蛋白塔帕辛形成混合二硫键，这种二聚体共轭物可编辑与MHC I类分子结合的肽库。在人类研究中由于塔帕辛突变或小鼠研究中由于ERp57缺失而无法形成共轭物的细胞中，肽负载受到阻碍。已观察到小鼠和人类系统之间存在细微差异。在此，我们探讨这些差异并扩展分析以研究ERp57氧化还原功能在MHC I类肽负载中的作用。我们在人类细胞中表明，在没有共轭物形成的情况下，MHC I类肽负载复合物中MHC I类的募集和/或稳定性受损，这与在小鼠细胞中的观察结果相似。然而，我们发现ERp57的α或α'结构域氧化还原位点的酶活性在肽负载中没有作用。我们的数据表明，ERp57在肽负载中的功能可能是由其他ERp57功能域或塔帕辛 - ERp57共轭物的组合特征引起的。
