Kukita Kazuharu, Tamura Yasuaki, Tanaka Tsutomu, Kajiwara Toshimitsu, Kutomi Goro, Saito Keita, Okuya Koichi, Takaya Akari, Kanaseki Takayuki, Tsukahara Tomohide, Hirohashi Yoshihiko, Torigoe Toshihiko, Furuhata Tomohisa, Hirata Koichi, Sato Noriyuki
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; and Department of Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; and
J Immunol. 2015 May 15;194(10):4988-96. doi: 10.4049/jimmunol.1303228. Epub 2015 Apr 13.
ERO1-α is an oxidizing enzyme that exists in the endoplasmic reticulum and is induced under hypoxia. It reoxidizes the reduced form of protein disulfide isomerase that has oxidized target proteins. We found that ERO1-α is overexpressed in a variety of tumor types. MHC class I H chain (HC) has two disulfide bonds in the α2 and α3 domains. MHC class I HC folding is linked to the assembly of MHC class I molecules because only fully disulfide-bonded class I HCs efficiently assemble with β2-microglobulin. In this study, we show that ERO1-α associates with protein disulfide isomerase, calnexin, and immature MHC class I before being incorporated into the TAP-1-associated peptide-loading complex. Importantly, ERO1-α regulates the redox state as well as cell surface expression of MHC class I, leading to alteration of susceptibility by CD8(+) T cells. Similarly, the ERO1-α expression within cancer cells was associated with the expression level of MHC class I in colon cancer tissues. Thus, the cancer-associated ERO1-α regulates the expression of the MHC class I molecule via oxidative folding.
ERO1-α是一种存在于内质网中的氧化酶，在缺氧条件下被诱导表达。它能将已氧化靶蛋白的蛋白质二硫键异构酶的还原形式重新氧化。我们发现ERO1-α在多种肿瘤类型中过度表达。MHC I类重链（HC）在α2和α3结构域中有两个二硫键。MHC I类HC折叠与MHC I类分子的组装相关，因为只有完全形成二硫键的I类HC才能有效地与β2-微球蛋白组装。在本研究中，我们表明ERO1-α在被整合到与TAP-1相关的肽负载复合物之前，与蛋白质二硫键异构酶、钙连蛋白和未成熟的MHC I类相关。重要的是，ERO1-α调节MHC I类的氧化还原状态以及细胞表面表达，导致CD8(+) T细胞敏感性改变。同样，癌细胞内的ERO1-α表达与结肠癌组织中MHC I类的表达水平相关。因此，与癌症相关的ERO1-α通过氧化折叠调节MHC I类分子的表达。
