Abstract
Although much progress has been made in identifying the signaling pathways that mediate viral RNA-induced apoptosis and activation of interferon-stimulated genes, the role that bacterial RNA plays in regulating these responses has remained undetermined. Herein, we identified bacterial RNA as a novel inducer of the apoptotic cell death. Unlike the parental cells, STAT1 and STAT2 mutants display apoptotic defects which were reversed by restoring the expression of wild type proteins. While STAT1 mutants lacking tyrosine-701 or a functional SH2 domain were effective as the wild-type protein in restoring the apoptotic response, the mutant carrying a point mutation at serine-727 of STAT1 was resistant to bacterial RNA-induced apoptosis. We also determined that the lack of apoptosis in the STAT1 and STAT2 mutants was correlated with the constitutive and inducible activation of apoptosis regulating proteins. Furthermore, we show that bacterial RNA induces transcriptional activation of STAT1, STAT2, IRF1, and ISGF3, which was impaired in STAT1 or STAT2 mutants. These observations suggested that the participation of STATs in regulating the apoptotic response is independent of their downstream functions as cytokine-induced transcriptional activators. In addition to bacterial immunity, the results presented here may also have implications in cellular pathophysiology and RNA-based therapy.
Highlights
Discriminating self from foreign is crucial to innate immunity that employs patterns recognition receptors (PRRs) to sense molecular patterns associated with pathogenic invaders
We show that bacterial RNA induces transcriptional activation of STAT1, STAT2, IRF1, and ISGF3, which was impaired in STAT1 or STAT2 mutants
Because DNA fragmentation is consistently used as a hallmark of apoptosis, we evaluated the potency of bacterial RNA to trigger genomic DNA fragmentation in HT1080 cells
Summary
Discriminating self from foreign is crucial to innate immunity that employs patterns recognition receptors (PRRs) to sense molecular patterns associated with pathogenic invaders. Of considerable interest are the recent findings that natural bacterial RNA and synthetic oligoribonucleotides can induce antigen-specific immunity, secretion of proinflammatory cytokines and type I interferons (IFNs) [5]-[18]. To exert their biological effects on targeted cells, IFNs bind to their receptors which results in the activation of intrinsic receptor tyrosine-kinase activity or receptor-associated kinases such as the Janus kinases (JAK) family of kinases [19]. IFN-γ induces the formation of STAT1 homodimers which in turn translocates into the nucleus, where they bind to distinct γ-activated sequence (GAS) in the promoters of target genes
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