The Unfolded Protein Response reveals eIF2α phosphorylation as a critical factor for direct MHC class I antigen presentation.

Abstract

Abstract Modifying direct Major Histocompatibility Class I (MHC I) antigen presentation is an attractive target for the treatment of various conditions including autoimmune diseases, chronic viral infections, and cancers. Disease perturbations alter the cellular environment, influencing the presentation of peptides to CD8+ T cells. The unfolded protein response (UPR) is a signaling pathway activated in response to unfolded proteins within the ER. Previous studies have established the relationship between the UPR and MHC I antigen presentation, but the exact mechanisms remained unknown. In this study, we utilized small inhibitory molecules to individual UPR pathway targets to investigate the effect on global MHC class I levels and specific peptide presentation. Preventing PERK pathway signaling and the resulting phosphorylation of eIF2α by GSK2656157 treatment did not change MHC I antigen presentation. However, treatment with salubrinal which has the opposite effect of GSK2656157, decreased both antigen presentation and overall cell-surface MHC I levels. Treatment with 4μ8C, an inhibitor of the IRE1α UPR activation pathway which prevents splicing of Xbp1 mRNA, also diminished MHC I antigen presentation. Unexpectedly, 4μ8C treatment led to an increase in eIF2α phosphorylation in addition to blocking IRE1α signaling. Given that salubrinal and 4μ8C increase phosphorylation levels of eIF2α while decreasing antigen presentation, we conclude that UPR signaling through PERK and the subsequent phosphorylation of eIF2α, results in a modest decrease in direct MHC I antigen presentation. These data suggest that the PERK pathway alters host antigen presentation centering on translational control by eIF2α.