Nagamine Brandy S, Godil Jamila, Dolan Brian P
Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331.
Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331
Immunohorizons. 2021 Mar 8;5(3):135-146. doi: 10.4049/immunohorizons.2100012.
The ability to modulate direct MHC class I (MHC I) Ag presentation is a desirable goal for the treatment of a variety of conditions, including autoimmune diseases, chronic viral infections, and cancers. It is therefore necessary to understand how changes in the cellular environment alter the cells' ability to present peptides to T cells. The unfolded protein response (UPR) is a signaling pathway activated by the presence of excess unfolded proteins in the endoplasmic reticulum. Previous studies have indicated that chemical induction of the UPR decreases direct MHC I Ag presentation, but the precise mechanisms are unknown. In this study, we used a variety of small molecule modulators of different UPR signaling pathways to query which UPR signaling pathways can alter Ag presentation in both murine and human cells. When signaling through the PERK pathway, and subsequent eIF2α phosphorylation, was blocked by treatment with GSK2656157, MHC I Ag presentation remain unchanged, whereas treatment with salubrinal, which has the opposite effect of GSK2656157, decreases both Ag presentation and overall cell-surface MHC I levels. Treatment with 4μ8C, an inhibitor of the IRE1α UPR activation pathway that blocks splicing of mRNA, also diminished MHC I Ag presentation. However, 4μ8C treatment unexpectedly led to an increase in eIF2α phosphorylation in addition to blocking IRE1α signaling. Given that salubrinal and 4μ8C lead to eIF2α phosphorylation and similar decreases in Ag presentation, we conclude that UPR signaling through PERK, leading to eIF2α phosphorylation, results in a modest decrease in direct MHC I Ag presentation.
调节直接的MHC I类（MHC I）抗原呈递的能力是治疗多种疾病（包括自身免疫性疾病、慢性病毒感染和癌症）的一个理想目标。因此，有必要了解细胞环境的变化如何改变细胞向T细胞呈递肽段的能力。未折叠蛋白反应（UPR）是一种在内质网中存在过量未折叠蛋白时被激活的信号通路。先前的研究表明，化学诱导UPR会降低直接的MHC I抗原呈递，但具体机制尚不清楚。在本研究中，我们使用了多种不同UPR信号通路的小分子调节剂，以探究哪些UPR信号通路可以改变小鼠和人类细胞中的抗原呈递。当通过PERK通路的信号传导以及随后的eIF2α磷酸化被GSK2656157处理阻断时，MHC I抗原呈递保持不变，而使用与GSK2656157具有相反作用的水杨醛处理，则会降低抗原呈递和整体细胞表面MHC I水平。用4μ8C（一种阻断mRNA剪接的IRE1α UPR激活通路抑制剂）处理也会减少MHC I抗原呈递。然而，4μ8C处理除了阻断IRE1α信号传导外，意外地还导致了eIF2α磷酸化增加。鉴于水杨醛和4μ8C会导致eIF2α磷酸化并使抗原呈递出现类似的降低，我们得出结论，通过PERK的UPR信号传导导致eIF2α磷酸化，会使直接的MHC I抗原呈递适度降低。
