Phosphoinositide 3-kinase regulates a subset of interferon-alpha-stimulated genes

Hjortsberg, Linn; Lindvall, Charlotta; Corcoran, Martin; Arulampalam, Velmurugesan; Chan, Dominic C.W.; Thyrell, Lena; Nordenskjöld, Magnus; Grandér, Dan; Pokrovskaja, Katja

doi:10.1016/j.yexcr.2006.10.022

Cited by 18 publications

(16 citation statements)

References 41 publications

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“…Examining the list for candidates with known functions in viral infection led us to the gene N-myc (and STAT) interactor (NMI). As an interferon stimulated gene (ISG) [35], a regulator of STAT signaling [13], and because of its involvement in virus-induced apoptosis [14], we chose to further investigate this putative target.…”

Section: Resultsmentioning

confidence: 99%

A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling

et al. 2013

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Torque teno viruses (TTVs) are a group of viruses with small, circular DNA genomes. Members of this family are thought to ubiquitously infect humans, although causal disease associations are currently lacking. At present, there is no understanding of how infection with this diverse group of viruses is so prevalent. Using a combined computational and synthetic approach, we predict and identify miRNA-coding regions in diverse human TTVs and provide evidence for TTV miRNA production in vivo. The TTV miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and are active in RISC. A TTV mutant defective for miRNA production replicates as well as wild type virus genome; demonstrating that the TTV miRNA is dispensable for genome replication in a cell culture model. We demonstrate that a recombinant TTV genome is capable of expressing an exogenous miRNA, indicating the potential utility of TTV as a small RNA vector. Gene expression profiling of host cells identifies N-myc (and STAT) interactor (NMI) as a target of a TTV miRNA. NMI transcripts are directly regulated through a binding site in the 3′UTR. SiRNA knockdown of NMI contributes to a decreased response to interferon signaling. Consistent with this, we show that a TTV miRNA mediates a decreased response to IFN and increased cellular proliferation in the presence of IFN. Thus, we add Annelloviridae to the growing list of virus families that encode miRNAs, and suggest that miRNA-mediated immune evasion can contribute to the pervasiveness associated with some of these viruses.

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Section: Resultsmentioning

confidence: 99%

A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling

et al. 2013

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“…The PI3 kinase pathway is also activated by IFN-α in various cell types and PI3K interacts with the JAK-STAT signaling pathway and aids in the activation of a limited number of genes(71). To assess if PI3K pathway was also involved in the induction of an antiangiogenic signature in IFN-treated EPCs/CACs, we performed similar experiments using a PI3K inhibitor.…”

Section: Resultsmentioning

confidence: 99%

The Detrimental Effects of IFN-α on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction

Thacker

Berthier

Mattinzoli

et al. 2010

The Journal of Immunology

118

113

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Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that IFN-α plays a crucial role in premature vascular damage in SLE. IFN-α alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). In this study, we demonstrate that IFN-α promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1α and β, IL-1R1, and vascular endothelial growth factor A, and upregulation of IL-1R antagonist and the decoy receptor IL-1R2. IL-1β promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-α. The beneficial effects from IL-1 are mediated, at least in part, by increases in EPC/CAC proliferation, by decreases in EPC/CAC apoptosis, and by preventing the skewing of CACs toward nonangiogenic pathways. IFN-α induces STAT2 and 6 phosphorylation in EPCs/CACs, and JAK inhibition abrogates the transcriptional antiangiogenic changes induced by IFN-α in these cells. Immunohistochemistry of renal biopsies from patients with lupus nephritis, but not anti-neutrophil cytoplasmic Ab-positive vasculitis, showed this pathway to be operational in vivo, with increased IL-1R antagonist, downregulation of vascular endothelial growth factor A, and glomerular and blood vessel decreased capillary density, compared with controls. Our study introduces a novel putative pathway by which type I IFNs may interfere with vascular repair in SLE through repression of IL-1–dependent pathways. This could promote atherosclerosis and loss of renal function in this disease.

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“…Type I IFNs can also cause the stabilization of other transcriptionally active STAT homodimers and heterodimers, the CRK-like protein (CRKL)-STAT5 heterodimer and nuclear factor-κB (NF-κB). Moreover, type I IFN signalling can trigger the phosphoinositide 3-kinase (PI3K) signal transduction cascade 113 . Finally, type I IFNs can promote the activation of the guanine nucleotide-exchange factor VAV1, thereby initiating a broad response that involves multiple transcription factors, including (but not limited to) the STAT1-STAT2 heterodimer, ELK1, MYC and tumour protein p53 (TP53) 5 .…”

Section: Box 2 | Signals Elicited By Type I Ifnsmentioning

confidence: 99%

Type I interferons in anticancer immunity

Zitvogel

Galluzzi²,

Kepp³

et al. 2015

Nat Rev Immunol

1,020

880

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Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells.

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Phosphoinositide 3-kinase regulates a subset of interferon-alpha-stimulated genes

Cited by 18 publications

References 41 publications

A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling

A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling

The Detrimental Effects of IFN-α on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction

Type I interferons in anticancer immunity

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