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ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells.

ABSTRACT: During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2. However, in this study, the constitutive expression of ISGs in human-derived senescent fibroblasts and in fibroblasts from a patient with Werner syndrome, which leads to premature aging, was mediated mainly by the unphosphorylated forms of STATs in the absence of INF production. Under homeostatic conditions, STAT1, STAT2, and IRF9 were localized to the nucleus of aged cells. Although knockdown of JAK1, a key kinase of STAT1 and STAT2, did not affect ISG expression or IFN-stimulated response element (ISRE)-mediated promoter activities in these senescent cells, knockdown of STAT1 or STAT2 decreased ISG expression and ISRE activities. These results suggest that the ISGF3 complex without clear phosphorylation is required for IFN-independent constitutive ISG transcription in senescent cells.

SUBMITTER: Yamagami M

PROVIDER: S-EPMC6237867 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells.

Yamagami Mari M Otsuka Motoyuki M Kishikawa Takahiro T Sekiba Kazuma K Seimiya Takahiro T Tanaka Eri E Suzuki Tatsunori T Ishibashi Rei R Ohno Motoko M Koike Kazuhiko K

NPJ aging and mechanisms of disease 20181115

During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of ...[more]

PMID: 30455980

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Project description:BackgroundSevere Acute Respiratory Syndrome (SARS) corona virus (CoV) infections are a serious public health threat because of their pandemic-causing potential. This work is the first to analyze mRNA expression data from SARS infections through meta-analysis of gene signatures, possibly identifying therapeutic targets associated with major SARS infections.MethodsThis work defines 37 gene signatures representing SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV2 infections in human lung cultures and/or mouse lung cultures or samples and compares them through Gene Set Enrichment Analysis (GSEA). To do this, positive and negative infectious clone SARS (icSARS) gene panels are defined from GSEA-identified leading-edge genes between two icSARS-CoV derived signatures, both from human cultures. GSEA then is used to assess enrichment and identify leading-edge icSARS panel genes between icSARS gene panels and 27 other SARS-CoV gene signatures. The meta-analysis is expanded to include five MERS-CoV and three SARS-CoV2 gene signatures. Genes associated with SARS infection are predicted by examining the intersecting membership of GSEA-identified leading-edges across gene signatures.ResultsSignificant enrichment (GSEA p<0.001) is observed between two icSARS-CoV derived signatures, and those leading-edge genes defined the positive (233 genes) and negative (114 genes) icSARS panels. Non-random significant enrichment (null distribution p<0.001) is observed between icSARS panels and all verification icSARSvsmock signatures derived from human cultures, from which 51 over- and 22 under-expressed genes are shared across leading-edges with 10 over-expressed genes already associated with icSARS infection. For the icSARSvsmock mouse signature, significant, non-random significant enrichment held for only the positive icSARS panel, from which nine genes are shared with icSARS infection in human cultures. Considering other SARS strains, significant, non-random enrichment (p<0.05) is observed across signatures derived from other SARS strains for the positive icSARS panel. Five positive icSARS panel genes, CXCL10, OAS3, OASL, IFIT3, and XAF1, are found across mice and human signatures regardless of SARS strains.ConclusionThe GSEA-based meta-analysis approach used here identifies genes with and without reported associations with SARS-CoV infections, highlighting this approach's predictability and usefulness in identifying genes that have potential as therapeutic targets to preclude or overcome SARS infections.

Dataset Information

ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells.

Publications

ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells.

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