title: RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma.
abstract: The immunoreceptor NKG2D originally identified in natural killer (NK) cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DL) is induced by the DNA damage response (DDR), which is often activated constitutively in cancer cells, revealing them to NK cells as a mechanism of immunosurveillance. Here, we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines that express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3(+/-);Eμ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared with Irf3(+/+);Eμ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117597 Singapore.
authors.forename: Adeline R
authors.initials: AR
authors.lastname: Lam
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
authors.forename: Nina Le
authors.initials: NL
authors.lastname: Bert
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
authors.forename: Samantha Sw
authors.initials: SS
authors.lastname: Ho
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117597 Singapore.
authors.forename: Yu J
authors.initials: YJ
authors.lastname: Shen
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
authors.forename: Li Fm
authors.initials: LF
authors.lastname: Tang
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Xiong
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
authors.forename: John L
authors.initials: JL
authors.lastname: Croxford
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117597 Singapore.|Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Saito-Asagi, Ibaraki, Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFREC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Christine X
authors.initials: CX
authors.lastname: Koo
authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Saito-Asagi, Ibaraki, Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFREC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: WPI Immunology Frontier Research Center (iFREC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.affiliation: Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, 117456, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117597 Singapore.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gasser
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics* / Q000502:physiology* / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D007157:Immunologic Surveillance; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D000099197:STING Protein
chemical_list: D004273:DNA, Neoplasm; D050838:Interferon Regulatory Factor-3; D008024:Ligands; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D017346:Protein Serine-Threonine Kinases; C494233:Irf3 protein, mouse; C527086:Klrk1 protein, mouse; C490521:Rae1 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse