Uchihara et al. showed that DNA damage-induced upregulation of HLA-I (di-HLA) cell surface presentation required antigen generation dependent on transcription and splicing, but not on IFN, mutational load, DNA repair, or HLA protein levels. In proliferative cells, DNA damage stimulated ATR to induce AKT-mTORC1-S6K signaling to promote a pioneer round of translation (PRT) prior to nonsense-mediated mRNA decay. Upregulation of di-HLA depended on the SMB8/9/10 immunoproteasome and TAP1/2 transporter. Analyses predicted that PRT-derived 9-mer peptides bind to HLA and may be immunogenic.
Contributed by Paula Hochman
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.
Author Info: (1) Signal Transduction Program, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan. (2) Department of Radiation Oncology, Faculty o
Author Info: (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) Signal Transduction Program, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan. (7) Signal Transduction Program, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan. (8) Hospital Campus Laboratory, Radioisotope Center, Central Institute of Radioisotope Science and Safety Management, Kyushu University, Fukuoka, Japan. (9) Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (10) Department of Radiation Oncology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta 10430, Indonesia. (11) Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan. (12) 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. (13) Signal Transduction Program, Gunma University, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan. Electronic address: shibata.at@gunma-u.ac.jp.
