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Non-Canonical Role of IKK? in the Regulation of STAT1 Phosphorylation in Antiviral Signaling.

ABSTRACT: Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addition to the well-known type I IFN-dependent pathway. I?B kinase ? (IKK?) is involved in antiviral signaling induced by dsRNA; however, its role is incompletely understood. Here, we explored the function of IKK? in RLR-mediated STAT1 phosphorylation. Silencing of IKK? markedly decreased the level of IFN-? and STAT1 phosphorylation inHeH response to dsRNA. However, the inhibition of IKK? did not alter the RLR signaling-mediated dimerization of interferon responsive factor 3 (IRF3) or the nuclear translocation of nuclear factor-?B (NF?B). These results suggest a non-canonical role of IKK? in RLR signaling. Furthermore, phosphorylation of STAT1 was suppressed by IKK? knockdown in cells treated with a specific neutralizing antibody for the type I IFN receptor (IFNAR) and in IFNAR-deficient cells. Collectively, the dual regulation of STAT1 by IKK? in antiviral signaling suggests a role for IKK? in the fine-tuning of antiviral signaling in response to non-self RNA.

SUBMITTER: Xing F

PROVIDER: S-EPMC5167405 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Non-Canonical Role of IKKα in the Regulation of STAT1 Phosphorylation in Antiviral Signaling.

Xing Fei F Matsumiya Tomoh T Shiba Yuko Y Hayakari Ryo R Yoshida Hidemi H Imaizumi Tadaatsu T

PloS one 20161219 12

Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addition to the well-known type I IFN-dependent pathway. IκB kinase α (IKKα) is involved in antiviral signal ...[more]

PMID: 27992555

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Project description:Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression at the transcriptional level, leading to activation of autocrine and paracrine JAK/STAT signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent on the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two other factors: IKKβ, a protein in the NF-kB signaling cascade, and p53. Activation of IL-6 by Notch required IKKβ function, but interestingly, did not engage canonical NF-κB signaling, in contrast to IL-6 activation by inflammatory agents such as tumor necrosis factor, which requires canonical NF-κB signaling. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, but restoring wildtype 53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced genome-wide transcriptomes from p53 wildtype and -mutated breast tumor cell lines differed extensively, and in a subset of genes upregulated by Notch in a p53-mutant cell line, upregulation was reduced by wildtype p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKβ in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output. 30 microarray samples consisting of MCF7 (ER+, wild-type p53, luminal type B breast cancer) and MDA-MB-231 (ER-, mutated p53, basal breast cancer) cells cultured on immobilized 1 μg/ml JAGGED1-Fc or 1 μg/ml DLL4-Fc or 1 μg/ml Fc control with or without 5 μM DAPT for 6 hours in 3 biological replicates.

Dataset Information

Non-Canonical Role of IKK? in the Regulation of STAT1 Phosphorylation in Antiviral Signaling.

Publications

Non-Canonical Role of IKKα in the Regulation of STAT1 Phosphorylation in Antiviral Signaling.

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