Double-Stranded RNA Induces Biphasic STAT1 Phosphorylation by both Type I Interferon (IFN)-Dependent and Type I IFN-Independent Pathways

Dempoya, Junichi; Matsumiya, Tomoh; Imaizumi, Tadaatsu; Hayakari, Ryo; Xing, Fei; Yoshida, Hidemi; Okumura, Ken; Satoh, Kei

doi:10.1128/jvi.01881-12

Cited by 43 publications

(45 citation statements)

References 48 publications

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“…Here we show that in-poly(I:C) is able to directly trigger apoptosis by a rapid and transient induction of Src-dependent STAT1 activation, indicating that in-poly(I:C) directly activates STAT1, independently from IFN-␤, which is produced afterward. Our data are consistent with those of Dempoya et al (42), who reported a poly(I:C)-induced STAT1 phosphorylation in both a type I IFN-dependent manner and a type I IFN-independent manner, depending on the period of time after the introduction of poly(I:C) into the cells.…”

Section: Discussionsupporting

confidence: 93%

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

Palchetti

Starace

Cesaris

et al. 2015

Journal of Biological Chemistry

104

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Section: Discussionsupporting

confidence: 93%

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

Palchetti

Starace

Cesaris

et al. 2015

Journal of Biological Chemistry

104

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“…These results suggest that IKKα mediates both type I IFN-dependent and independent STAT1 phosphorylation in RLR signaling. Introduction of poly I:C in IFNAR-deficient U5A cells resulted in type I IFN-independent STAT1 phosphorylation (Fig 4B), as shown previously [14]. Silencing IKKα suppressed the level of phosphorylated STAT1 in response to poly I:C in U5A cells, indicating the involvement of IKKα in type I IFN-independent STAT1 phosphorylation activated by RLR signaling.…”

Section: Resultssupporting

confidence: 87%

“…Transient transfections of HeLa and U5A cells were performed as previously described [14]. Briefly, the cells were seeded at a density of 1.5×10 5 or 2.5×10 5 cells per well, respectively, in 12-well culture plates for 16 to 20 h prior to transfection and grown to 70–80% confluency.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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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 signaling induced by dsRNA; however, its role is incompletely understood. Here, we explored the function of IKKα in RLR-mediated STAT1 phosphorylation. Silencing of IKKα markedly decreased the level of IFN-β and STAT1 phosphorylation inHeH response to dsRNA. However, the inhibition of IKKα did not alter the RLR signaling-mediated dimerization of interferon responsive factor 3 (IRF3) or the nuclear translocation of nuclear factor-κB (NFκB). These results suggest a non-canonical role of IKKα in RLR signaling. Furthermore, phosphorylation of STAT1 was suppressed by IKKα 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 IKKα in antiviral signaling suggests a role for IKKα in the fine-tuning of antiviral signaling in response to non-self RNA.

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“…Lysates were cleared by centrifugation at 12,000×g for 10 min at 4°C. Sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), electro-blotting, and immunodetection were performed as described previously [17]. The primary antibodies used in this study were as follows: anti-TRAF3 and anti-TRAF5 antibodies (Santa Cruz Biotechnology), anti-RIG-I and anti-MAVS antibodies (Enzo Life Sciences, Farmingdale, NY, USA), and an anti-β-actin antibody (Sigma-Aldrich).…”

Section: Immunoblot Analysesmentioning

confidence: 99%

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

Chiba

Matsumiya

Satoh

et al. 2015

Biochemical and Biophysical Research Communications

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Upon viral infection, the cytoplasmic viral sensor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA to activate antiviral signaling to induce type I interferon (IFN).RIG-I-like receptors (RLRs) activate antiviral signaling in a tissue-specific manner. The molecular mechanism underlying antiviral signaling in the respiratory system remains unclear.We studied antiviral signaling in the lower respiratory tract (LRT), which is the site of many harmful viral infections. Epithelial cells of the LRT can be roughly divided into two groups: bronchial epithelial cells (BECs) and pulmonary alveolar epithelial cells (AECs). These two cell types exhibit different phenotypes; therefore, we hypothesized that these cells may play different roles in antiviral innate immunity. We found that BECs exhibited higher antiviral activity than AECs. TNF receptor-associated factor 3 (TRAF3) has been shown to be a crucial molecule in RLR signaling. The expression levels of TRAF3 and TRAF5, which have conserved domains that are nearly identical, in the LRT were examined. We found that the bronchus exhibited the highest expression levels of TRAF3 and TRAF5 in the LRT. These findings suggest the importance of the bronchus in antiviral innate immunity in the LRT and indicate that TRAF3 and TRAF5 may contribute to RLR signaling.

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Double-Stranded RNA Induces Biphasic STAT1 Phosphorylation by both Type I Interferon (IFN)-Dependent and Type I IFN-Independent Pathways

Cited by 43 publications

References 48 publications

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

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

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

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