Hypoxia-inducible ERO1-α acts as a member of pre-peptide loading complex and regulates immune responses in the context of MHC class I and class II molecules

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The human endoplasmic reticulum oxidoreductin like(ERO1-α) is an oxidizing enzyme that exists in endoplasmic reticulum and is induced under stress environment such as the hypoxia. It regulates a redox state of various kinds of protein through protein disulfide isomerase(PDI). Interestingly, although the expression of ERO1-α in the normal tissue was comparatively limited, various types of cancer cells expressed the large amount of ERO1-α. As the major histocompatibility complex(MHC) class I molecule carries the intramolecular disulfide bonds, we examined whether the hERO1-La plays a role in the oxidative folding and the expression of MHC class I molecules in cancer cells. We established ERO1-α overexpressed and knockdown SW480 cells. As a result, surface expression of MHC class I molecule was up-regulated in the ERO1-α-overexpressed SW480 and down-regulated in the ERO1-α knockdown SW480. Moreover, we have observed that the oxidized form of MHC class I was increased in the hERO1-La-overe … More xpressed SW480. In addition, we have observed that the hERO1-La knockdown SW480 have an impaired response to cytotoxic T lymphocyte(CTL). Interestingly, ERO1-α is highly expressed in the antigen presenting cells such as B cells and dendritic cells among the normal cells. As the major histocompatibility complex(MHC) class II molecule also carries the intramolecular disulfide bonds, we examined whether the ERO1-α plays a role in the oxidative folding and the expression of MHC class II molecules in B cell line. Because human B cell lymphoma line BALL-1 showed high expression of ERO1-α, we generated BALL-1 cells with ERO1-α knockdown using shRNA. As a result, surface expression of MHC class II molecule was down-regulated in the ERO1-Lα-knockdown cells compared to wild type cells. Moreover, knockdown of hERO1-α resulted in the decrease of oxidized form of MHC class II, thereby decreasing the stable peptide-MHC class II complexes. These data suggested that ERO1-α may play an important role in the immune responses against foreign antigens. These data suggested that the ERO1-α regulates immune response via modulation of MHC class I and class II expression and the quality. Less