Overexpression of the transcription factor Sp1 activates the OAS-RNAse L-RIG-I pathway.
Deregulated expression of oncogenes or transcription factors such as specificity protein 1 (Sp1) is observed in many human cancers and plays a role in tumor maintenance. Paradoxically in untransformed cells, Sp1 overexpression induces late apoptosis but the early intrinsic response is poorly characterized. In the present work, we studied increased Sp1 level consequences in untransformed cells and showed that it turns on an early innate immune transcriptome. Sp1 overexpression does not activate known cellular stress pathways such as DNA damage response or endoplasmic reticulum stress, but induces the activation of the OAS-RNase L pathway and the generation of small self-RNAs, leading to the upregulation of genes of the antiviral RIG-I pathway at the transcriptional and translational levels. Finally, Sp1-induced intrinsic innate immune response leads to the production of the chemokine CXCL4 and to the recruitment of inflammatory cells in vitro and in vivo. Altogether our results showed that increased Sp1 level in untransformed cells constitutes a novel danger signal sensed by the OAS-RNase L axis leading to the activation of the RIG-I pathway. These results suggested that the OAS-RNase L-RIG-I pathway may be activated in sterile condition in absence of pathogen.
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Valéryane
V
Dupuis-Maurin
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Lilia
L
Brinza
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Joël
J
Baguet
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Emilie
E
Plantamura
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Stéphane
S
Schicklin
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Solène
S
Chambion
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Claire
C
Macari
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Martine
M
Tomkowiak
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Emmanuelle
E
Deniaud
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Yann
Y
Leverrier
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Jacqueline
J
Marvel
Centre International de Recherche en Infectiologie, INSERM U111-CNRS UMR5308, Université de Lyon 1, ENS de Lyon, Lyon, France.
Marie-Cécile
MC
Michallet
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D051379:Mice; D010978:Platelet Factor 4 / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome; D015854:Up-Regulation; D018116:Vesiculovirus / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D016329:Sp1 Transcription Factor; D010978:Platelet Factor 4; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases