2. Academic Validation
  3. 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

  • 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

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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