TY - JOUR
T1 - DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production
AU - Uchihara, Yuki
AU - Permata, Tiara Bunga Mayang
AU - Sato, Hiro
AU - Kawabata-Iwakawa, Reika
AU - Katada, Sayako
AU - Gu, Wenchao
AU - Kakoti, Sangeeta
AU - Yamauchi, Motohiro
AU - Kato, Reona
AU - Gondhowiardjo, Soehartati
AU - Hosen, Naoki
AU - Yasuhara, Takaaki
AU - Shibata, Atsushi
N1 - Funding Information:
We thank Prof. Penny A. Jeggo for critical discussion throughout the project. We also thank Tatsuaki Kurosaki for discussions in this study. The authors would like to thank Akiko Shibata, Yoko Hayashi, Yasuyo Sekiguchi, Hiroko Iino, Naho Takashima, Yukihiko Yoshimatsu, and Itaru Sato for assisting with the laboratory work. This work was supported by JSPS KAKENHI grant numbers JP17H04713, JP20H04879, JP20K21536, JP21H05504, and JP21H03596; the Takeda Science Foundation; the Sumitomo Foundation; Suntory Foundation for Life Sciences Bioorganic Research Institute; Kobayashi Foundation for Cancer Research; Foundation for Promotion of Cancer Research; Gunma Foundation for Medicine and Health Science; and the National Cancer Center Research and Development Fund (2021-A-8) to A.S. This work was also supported by JSPS KAKENHI grant number JP21K17888 to Y.U. This study is supported by the Takeda Science Foundation, The Uehara Memorial Foundation, the Astellas Foundation for Research on Metabolic Disorders, the Kanae Foundation for the Promotion of Medical Science, the Yasuda Memorial Medicine Foundation, the Nakajima Foundation, and the Sumitomo Foundation to H.S. This work was also supported by Gunma University for the promotion of scientific research and Program of the Network-Type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukushima Medical University. A part of this study was conducted through the Joint Usage/Research Center Program of the Radiation Biology Center, Kyoto University. A.S. designed the study with Y.U. and T.Y. The tissue culture work, including immunoblotting, FCM, and RNA-seq, was performed by Y.U. T.B.M.P. H.S. S. Kakoti, W.G. and A.S. RNA-seq and its related bioinformatics analyses were performed by Y.U. with support from R.K.-I. and S. Katada. Y.U. and A.S. summarized all the data for the figures and tables and wrote the manuscript with support from S.G. M.Y. R.K. N.H. and T.Y. All authors reviewed the manuscript. The study was supervised by A.S. The authors declare no competing interests.
Funding Information:
We thank Prof. Penny A. Jeggo for critical discussion throughout the project. We also thank Tatsuaki Kurosaki for discussions in this study. The authors would like to thank Akiko Shibata, Yoko Hayashi, Yasuyo Sekiguchi, Hiroko Iino, Naho Takashima, Yukihiko Yoshimatsu, and Itaru Sato for assisting with the laboratory work. This work was supported by JSPS KAKENHI grant numbers JP17H04713 , JP20H04879 , JP20K21536 , JP21H05504 , and JP21H03596 ; the Takeda Science Foundation ; the Sumitomo Foundation ; Suntory Foundation for Life Sciences Bioorganic Research Institute ; Kobayashi Foundation for Cancer Research ; Foundation for Promotion of Cancer Research ; Gunma Foundation for Medicine and Health Science ; and the National Cancer Center Research and Development Fund ( 2021-A-8 ) to A.S. This work was also supported by JSPS KAKENHI grant number JP21K17888 to Y.U. This study is supported by the Takeda Science Foundation , The Uehara Memorial Foundation , the Astellas Foundation for Research on Metabolic Disorders , the Kanae Foundation for the Promotion of Medical Science , the Yasuda Memorial Medicine Foundation , the Nakajima Foundation , and the Sumitomo Foundation to H.S. This work was also supported by Gunma University for the promotion of scientific research and Program of the Network-Type Joint Usage / Research Center for Radiation Disaster Medical Science of Hiroshima University , Nagasaki University , and Fukushima Medical University . A part of this study was conducted through the Joint Usage/Research Center Program of the Radiation Biology Center, Kyoto University.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/7/21
Y1 - 2022/7/21
N2 - 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.
AB - 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.
KW - ATR
KW - DNA damage
KW - antigen production
KW - di-HLA presentation
KW - human leukocyte antigen
KW - nonsense-mediated mRNA decay
KW - pioneer round of translation
UR - http://www.scopus.com/inward/record.url?scp=85134780564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85134780564&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2022.04.030
DO - 10.1016/j.molcel.2022.04.030
M3 - Article
C2 - 35594857
AN - SCOPUS:85134780564
SN - 1097-2765
VL - 82
SP - 2557-2570.e7
JO - Molecular Cell
JF - Molecular Cell
IS - 14
ER -