title: Control of FoxO4 Activity and Cell Survival by TRIM22 Directs TLR3-Stimulated Cells Toward IFN Type I Gene Induction or Apoptosis.
abstract: Activation of innate immune response, induced after the recognition of double-stranded RNA (dsRNA), formed during replication of most viruses, results in intracellular signaling cascades ultimately culminating in the expression of type I interferon (IFN). In this study, we provide the first evidence that FoxO4 triggers the activation of the innate immune signaling pathway in coupling stimulation of TLR3 and RIG-like receptors by the synthetic dsRNA analog, poly(I:C), to IFN-β and IFN-induced gene induction, whereas knockdown of FoxO4 had opposite effects. Similar effects of FoxO4 were observed during paramyxovirus-mediated IFN-β transcriptional induction. We further found that knockdown of FoxO4 did not affect IRF3 and NF-κB activation by poly(I:C), suggesting that FoxO4 would act downstream in the signaling pathway. In addition, we show that the IFN-induced TRIM22 ubiquitin ligase targets FoxO4 and antagonizes its activity through an unrelated ubiquitin/autophagosomic-lysosomal pathway. Unexpectedly, TRIM22 knockdown strongly sensitizes cells to dsRNA-induced caspase-dependent apoptosis, as early as 2 h after poly(I:C) stimulation, concomitantly to the inhibition of the expression of the antiapoptotic protein, Bcl-2, indicating that TRIM22 might be a key factor for controlling the cell survival after TLR3 stimulation. Taken together, our data demonstrate that the regulation of FoxO4 protein expression and cell survival by TRIM22 controls TLR3-mediated IFN type I gene induction, preventing excessive antiviral response through dsRNA-induced apoptosis.
authors.affiliation: 1 CNRS, UMR5235, DIMNP, University of Montpellier 2 , Montpellier, France .|2 CNRS UMR5236, University of Montpellier 1 and 2 , Montpellier, France .
authors.forename: Alexandra
authors.initials: A
authors.lastname: Oteiza
authors.affiliation: 1 CNRS, UMR5235, DIMNP, University of Montpellier 2 , Montpellier, France .|2 CNRS UMR5236, University of Montpellier 1 and 2 , Montpellier, France .
authors.forename: Nadir
authors.initials: N
authors.lastname: Mechti
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012330:RNA, Double-Stranded / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D000070584:Tripartite Motif Proteins; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012330:RNA, Double-Stranded; D012097:Repressor Proteins; C495344:TLR3 protein, human; C094314:TRIM22 protein, human; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D016899:Interferon-beta; D011070:Poly I-C