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ERAP1 as a regulator of the immunopeptidome, proteome and cellular homeostasis of cancer cells. A375 Immunopeptidome, Part I.

ABSTRACT: Endoplasmic reticulum aminopeptidase 1 (ERAP1) metabolizes peptides inside the ER and shapes the peptide repertoire available for binding to Major Histocompatibility Class I molecules (MHC-I). Moreover, it may have additional effects on cellular homeostasis, which have not been explored. To address these questions, we utilized genetic silencing of ERAP1 expression as well as a selective allosteric ERAP1 inhibitor to probe changes in the immunopeptidome and proteome of the A375 melanoma cancer cell line. We observed significant immunopeptidome shifts upon both methods of ERAP1 functional disruption, which were distinct for each method. Both methods of inhibition led to mild enhancement of cancer cell killing by stimulated human PBMCs from a healthy donor. ERAP1 functional disruption also resulted in significant proteomic alterations that focused on pathways related to metabolism and cellular stress. Similar proteomic changes were also observed in the leukemia cell line THP-1. Biochemical analyses suggested that ERAP1 inhibition affected ER stress, reactive oxygen species production and mitochondrial metabolism. Although the proteomics shifts were significant, their potential in shaping immunopeptidome shifts was limited since only 15.8% of differentially presented peptides belonged to proteins with altered expression and 4.8% of proteins with altered expression were represented in the immunopeptidome shifts. Taken together, our findings suggest that inhibition of ERAP1 can generate unique immunopeptidomes, primarily due to altered peptide processing in the ER, but also induce compensatory changes in the cellular proteome and metabolic state which may have additional effects on cancer cells.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Martina Samiotaki

LAB HEAD: Efstratios Stratikos

PROVIDER: PXD054491 | Pride | 2025-05-23

REPOSITORIES: Pride

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Project description:Ulcerative colitis (UC) is a life-threatening heterogeneous condition characterized by inflammation of the colon. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is essential for antigen processing and immune regulation, however, its specific role in UC pathogenesis and therapeutic response remains unclear. This study aimed to investigate the role of ERAP1 in the response to sulfasalazine, a standard treatment for UC, using an ERAP1-heterozygous (ERAP1⁺/⁻) mouse model susceptible to colitis. Wild-type (WT) and ERAP1+/− mice were treated with 2.5% dextran sulfate sodium (DSS) to induce colitis, followed by sulfasalazine administration. Colitis severity was assessed through histopathology. Immune cell populations, including neutrophils, dendritic cells, T cells, and NK1.1+ cells, were analyzed using flow cytometry. RNA sequencing of colonic tissues was performed to assess gene expression changes associated with reduced ERAP1 expression. ERAP1+/− mice exhibited more severe DSS-induced colitis, with greater weight loss and increased mucosal damage compared to WT mice. In addition, ERAP1+/− colitis mice showed marked changes in peripheral blood and intestinal intraepithelial lymphocyte (IELs) immune cell infiltration after sulfasalazine treatment. RNA sequencing identified 428 differentially expressed genes between ERAP1⁺/⁻ and WT mice. Among these, 28 genes were previously associated with colitis or colorectal cancer, of which 11 were upregulated and 17 downregulated in ERAP1⁺/⁻ mice. RT-qPCR analysis further confirmed that the expression of Anxa9, Atp2a1, and Hepacam2 was significantly elevated in ERAP1⁺/⁻ mice following sulfasalazine treatment, suggesting a differential therapeutic response. Collectively, our study demonstrates that partial ERAP1 deficiency exacerbates DSS-induced colitis by promoting immune dysregulation and altering the expression of inflammation-related genes. These findings suggest that reduced ERAP1 expression may impair the therapeutic efficacy of sulfasalazine. Therefore, ERAP1 may serve as a key regulator in the pathogenesis of UC and a potential target for therapy.

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ERAP1 as a regulator of the immunopeptidome, proteome and cellular homeostasis of cancer cells. A375 Immunopeptidome, Part I.

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