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DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production
Molecular Cell ( IF 16.0 ) Pub Date : 2022-05-19 , DOI: 10.1016/j.molcel.2022.04.030
Yuki Uchihara 1 , Tiara Bunga Mayang Permata 2 , Hiro Sato 3 , Reika Kawabata-Iwakawa 4 , Sayako Katada 5 , Wenchao Gu 1 , Sangeeta Kakoti 1 , Motohiro Yamauchi 6 , Reona Kato 7 , Soehartati Gondhowiardjo 2 , Naoki Hosen 8 , Takaaki Yasuhara 9 , Atsushi Shibata 1
Affiliation  

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 potentially immunogenic. Therefore, DNA damage signaling produces immunogenic antigens by utilizing the machinery of PRT/NMD.



中文翻译:

DNA 损伤通过刺激首轮翻译相关抗原产生来促进 HLA I 类呈递

人类白细胞抗原 (HLA) 在细胞表面的抗原呈递对于将免疫信号转导至细胞毒性 T 淋巴细胞至关重要。DNA 损伤上调 HLA I 类呈递;但是,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,证明抗原产生是必不可少的。此外,我们表明 di-HLA 呈现需要 ATR、AKT、mTORC1 和 p70-S6K 信号传导。值得注意的是,在无义介导的 mRNA 衰变 (NMD) 之前启动先锋轮翻译 (PRT) 的因素 CBP20 的消耗消除了 di-HLA 呈递,表明双抗原生产需要 PRT。RNA-seq 分析表明 DNA 损伤以 ATR 依赖性方式减少 NMD 转录物,与启动 PRT/NMD 时对 ATR 的要求一致。最后,生物信息学分析确定 PRT 衍生的 9-mer 肽与 HLA 结合并具有潜在的免疫原性。因此,DNA 损伤信号通过利用 PRT/NMD 机制产生免疫原性抗原。

更新日期:2022-05-19
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