title: Decreased Dicer expression elicits DNA damage and up-regulation of MICA and MICB.
abstract: RNA interference (RNAi) acts constitutively to silence the innate immune response, and innate immunity genes are misregulated in Dicer-deficient Caenorhabditis elegans. Here, we show that inhibition of Dicer expression by RNAi in human cells up-regulates major histocompatibility complex class I-related molecules A and B (MICA and MICB). MICA and MICB are innate immune system ligands for the NKG2D receptor expressed by natural killer cells and activated CD8(+)T cells. We reveal that knockdown of Dicer elicits DNA damage. Up-regulation of MICA and MICB by Dicer knockdown is prevented by pharmacologic or genetic inhibition of DNA damage pathway components, including ataxia telangiectasia mutated (ATM) kinase, ATM- and Rad3-related kinase, or checkpoint kinase 1. Therefore we conclude that up-regulation of MICA and MICB is the result of DNA damage response activation caused by Dicer knockdown. Our results suggest that RNAi is indirectly linked to the human innate immune system via the DNA damage pathway.
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases of the State Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China. tang_kaifu@yahoo.com.cn
authors.forename: Kai-Fu
authors.initials: KF
authors.lastname: Tang
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.forename: Jia
authors.initials: J
authors.lastname: Cao
authors.forename: Gui-Li
authors.initials: GL
authors.lastname: Zeng
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: He
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000276:immunology; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004722:Endoribonucleases / Q000235:genetics* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D043244:Ribonuclease III; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C000605876:chk-1 protein, C elegans; C456840:rad3 protein, S pombe; D004722:Endoribonucleases; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases