DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production

  • Mol Cell. 2022 Jul 21;82(14):2557-2570.e7. 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  10
Affiliations
  • 1. Signal Transduction Program, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan.
  • 2. Department of Radiation Oncology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta 10430, Indonesia.
  • 3. Department of Radiation Oncology, Gunma University, Maebashi, Gunma, Japan.
  • 4. Division of Integrated Oncology Research, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan.
  • 5. Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 6. Hospital Campus Laboratory, Radioisotope Center, Central Institute of Radioisotope Science and Safety Management, Kyushu University, Fukuoka, Japan.
  • 7. Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 8. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan.
  • 9. Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
  • 10. Signal Transduction Program, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan. Electronic address: [email protected].
PMID: 35594857 DOI: 10.1016/j.molcel.2022.04.030
Abstract

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.

Keywords
ATR; DNA damage; antigen production; di-HLA presentation; human leukocyte antigen; nonsense-mediated mRNA decay; pioneer round of translation.
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