Cancer-Associated Oxidase ERO1-α Regulates the Expression of MHC Class I Molecule via Oxidative Folding

Abstract

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

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

“…Ero1α is recognized as a cancer‐associated oxidase because its expression is significantly elevated in many cancers such as breast (Kutomi et al , ), gastrointestinal (Battle et al , ), and pancreatic (Kukita et al , ) cancers. Moreover, Ero1α enhances the expression of major histocompatibility complex class I antigen (Kukita et al , ), vascular endothelial growth factor (Tanaka et al , ), and programmed death‐ligand 1 (Tanaka et al , ) via oxidative folding to promote tumor growth. Notably, Fam20C‐dependent phosphorylation of secreted proteins is necessary for the proper adhesion, migration, and invasion of cancer cells (Tagliabracci et al , ).…”

“…Ero1α utilizes oxygen as the final electron acceptor for de novo disulfide bond formation and transfers disulfides to PDI, which directly catalyzes disulfide formation in reduced substrates (Mezghrani et al , ; Tu & Weissman, ; Sevier & Kaiser, ). Ero1α is upregulated under hypoxic conditions (May et al , ), highly expressed in many cancers (Battle et al , ; Kukita et al , ), and involved in calcium flux and cell apoptosis (Li et al , ; Chin et al , ).…”

High expression of IRE1 in lung adenocarcinoma is associated with a lower rate of recurrence

“…For example, expression of the ER stress chaperon protein calreticulin in NSCLC was reported to correlate with a favorable prognosis (21). In addition, expression of ER stress-related genes in tumor cells may promote the activity of anti-tumor immune cells (21,22). Our experimental results are consistent with these reports.…”

Overview of Research and Development for Anticancer Drugs

“…To cope with ER stress, eukaryotic cells activate the unfolded protein response to facilitate cancer proliferation by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation, thus targeting these ER hosted dynamic signaling network can lead increase or decrease of ROS levels in cancer cells and thereby influence overall cell fate [27]. These ER targets include inositol-requiring enzyme-1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor-6 [26], glucose-regulated proteins [28] [29], heat shock proteins [29]- [31], endoplasmic reticulum disulfide oxidase [32] [33], peroxiredxins and glutathione peroxidases [34]. Efforts to develop small-molecule inhibitors, or monoclonal antibody/non-antibody proteins/vaccines targeting to these targets are underway, several of which have shown high potency and as well as selectivity in preclinical or clinical trials [27] [35].…”