DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production
DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production
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DOI：
10.1016/j.molcel.2022.04.030
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发表时间：
2022-07-21
期刊：
影响因子：
16
通讯作者：
Shibata, Atsushi
中科院分区：
文献类型：
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作者：
Uchihara, Yuki;Permata, Tiara Bunga Mayang;Shibata, Atsushi
人类白细胞抗原 (HLA) 在细胞表面的抗原呈递对于免疫信号向细胞毒性 T 淋巴细胞的转导至关重要。 DNA 损伤上调 HLA I 类呈递；然而，其机制尚不清楚。在这里，我们表明 DNA 损伤诱导的 HLA (di-HLA) 呈递需要免疫蛋白酶体 PSMB8/9/10 和抗原转运蛋白 TAP1/2，这证明抗原的产生是必不可少的。此外，我们表明 di-HLA 呈递需要 ATR、AKT、mTORC1 和 p70-S6K 信号传导。值得注意的是，CBP20 是在无义介导的 mRNA 衰减 (NMD) 之前启动首轮翻译 (PRT) 的因子，CBP20 的耗尽会消除二 HLA 呈递，表明二抗原的产生需要 PRT。 RNA-seq 分析表明，DNA 损伤以 ATR 依赖性方式减少 NMD 转录本，这与 PRT/NMD 启动时对 ATR 的要求一致。最后，生物信息学分析确定 PRT 衍生的 9 聚体肽与 HLA 结合并且具有潜在的免疫原性。因此，DNA 损伤信号传导利用 PRT/NMD 机制产生免疫原性抗原。
Antigen presentation by the human leukocyte antigen (HLA) on the cell surface is critical for the transduction of the immune signal toward cytotoxic T lymphocytes. DNA damage upregulates HLA class I presentation; however, the mechanism is unclear. Here, we show that DNA-damage-induced HLA (di-HLA) presentation requires an immunoproteasome, PSMB8/9/10, and antigen-transporter, TAP1/2, demonstrating that antigen production is essential. Furthermore, we show that di-HLA presentation requires ATR, AKT, mTORC1, and p70-S6K signaling. Notably, the depletion of CBP20, a factor initiating the pioneer round of translation (PRT) that precedes nonsense-mediated mRNA decay (NMD), abolishes di-HLA presentation, suggesting that di-antigen production requires PRT. RNA-seq analysis demonstrates that DNA damage reduces NMD transcripts in an ATR-dependent manner, consistent with the requirement for ATR in the initiation of PRT/ NMD. Finally, bioinformatics analysis identifies that PRT-derived 9-mer peptides bind to HLA and are poten-tially immunogenic. Therefore, DNA damage signaling produces immunogenic antigens by utilizing the ma-chinery of PRT/NMD.