STAT2-dependent induction of RNA adenosine deaminase ADAR1 by type I interferon differs between mouse and human cells in the requirement for STAT1

George, Cyril X.; Samuel, Charles E.

doi:10.1016/j.virol.2015.08.001

Cited by 22 publications

(21 citation statements)

References 52 publications

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“…In present study, we observed ADAR1 expression was induced after H 2 O 2 treatment in NCM. Previous reports revealed a STAT-2 dependent process of transcriptional activation of IFN-induced ADAR1 expression in mouse embryo fibroblast cells38. In our study, we confirmed H 2 O 2 induced ADAR1 expression in NCM was also STAT-2 dependent.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation

Wang

Men

Xie

et al. 2016

Sci Rep

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Reactive oxygenation species (ROS) generated from reperfusion results in cardiac injury through apoptosis and inflammation, while PKR has the ability to promote apoptosis and inflammation. The aim of the study was to investigate whether PKR is involved in hydrogen peroxide (H2O2) induced neonatal cardiac myocytes (NCM) injury. In our study, NCM, when exposed to H2O2, resulted in persistent activation of PKR due to NCM endogenous RNA. Inhibition of PKR by 2-aminopurine (2-AP) or siRNA protected against H2O2 induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H2O2 induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H2O2 induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H2O2 treatment through STAT-2 dependent pathway. By gain and loss of ADAR1 expression, we confirmed ADAR1 modulated PKR activity. Therefore, we concluded inhibition of PKR protected against H2O2-induced injury by attenuating apoptosis and inflammation. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H2O2 to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.

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Section: Discussionsupporting

confidence: 89%

Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation

Wang

Men

Xie

et al. 2016

Sci Rep

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“…Previous studies suggest that ADAR1 expression is enhanced by inflammatory cytokine signaling that activates STAT binding to the ADAR1 promoter (George et al, 2008; George and Samuel, 2015). Thus, cytokine receptor and downstream target gene expression were analyzed by RNA-seq of fluorescence-activated cell sorting (FACS)-purified normal, CP, and BC progenitors (Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…Transcripts of inflammatory cytokine-associated receptor genes, which signal through the JAK-STAT pathway, and their downstream target genes were increased in BC compared with normal and CP progenitors (Figures 1A and S1A–E). Compared with CP, BC progenitors harbored increased levels of IFNγR1 and IL-3Rα, which can signal through JAK2 and activate ADAR1 transcription by binding of STATs to the ADAR1 promoter (Figure 1B) (George and Samuel, 2015). In addition, BC CML harbored increased expression of JAK/STAT signaling pathway genes and JAK2 transcripts compared with normal progenitors (Figures 1C and S1F).…”

Section: Resultsmentioning

confidence: 99%

ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

et al. 2016

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SUMMARY Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912 mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small molecule tool compound antagonizes ADAR1’s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSC with active JAK2 signaling.

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“…Furthermore, neither Stat1 Ϫ/Ϫ nor Stat2 Ϫ/Ϫ MEFs showed IFN-induced editing. ADAR1 is induced by IFN through JAK-STAT signaling, both in mouse MEFs and human 2fTGH cells (36,38). Likewise, PKR is induced by IFN through JAK-STAT signaling (14,15).…”

Section: Discussionmentioning

confidence: 99%

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

George

Ramaswami

et al. 2016

Journal of Biological Chemistry

Self Cite

128

105

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One mechanism by which cells respond to different forms of stress is the global reduction of protein synthesis (1). Phosphorylation of protein synthesis initiation factor eIF2␣ on serine 51 is recognized as a universal mechanism of translation suppression in response to cellular stress (1, 2). Four different protein kinases are activated in mammalian cells in response to different stresses, and they all catalyze Ser-51 phosphorylation of eIF2␣ as follows: protein kinase regulated by RNA (PKR) activated by double-stranded RNA; heme-regulated inhibitor kinase activated by hemin deficiency and oxidative stress; general control non-derepressible kinase 2 (GCN2) activated by amino acid deficiency; and PKR-like endoplasmic reticulum kinase activated by protein misfolding and endoplasmic reticulum stress (2, 3). The global inhibition of translation in cultured cells mediated by eIF2␣ phosphorylation is linked to the formation of stress granules (SG), 2 cytoplasmic aggregates of stalled 40S ribosomal subunit-containing translation initiation complexes, translation initiation factors, and RNA-binding proteins, including Ras GTPase-activating protein-Src homology 3 domain binding protein 1 G3BP1 (4). Stress granule formation is one hallmark of virus infection, serving as an index of innate immune responses, and is PKR-dependent for a variety of viruses (5-8).A cornerstone of innate antiviral immunity is the interferon (IFN) system (9, 10). IFNs act through the transcriptional induction of IFN-stimulated genes that encode products responsible for the biological activities of IFNs, including the ability of IFNs to inhibit virus multiplication and enhance apoptosis (11-13). Among the IFN-stimulated gene products is the PKR kinase induced by IFN through canonical JAK-STAT signaling (14 -16). PKR is activated by binding dsRNA that mediates PKR dimerization and autophosphorylation; activated PKR catalyzes the phosphorylation of eIF2␣ (17)(18)(19)(20). In the case of several viruses, PKR displays antiviral and proapoptotic activities (12,21,22). Exemplified by measles virus, PKR sufficiency and kinase activation correlate with reduced virus growth (23, 24), enhanced induction of IFN␤ (25,26), increased SG responses (7), and increased cytotoxicity and apoptosis (27,28). The central importance of PKR furthermore is illustrated both by the large number of viruses that encode gene products that antagonize PKR activation and function, and by the effects of genetic disruption of the Pkr gene (12,13,29).Similar to PKR, ADAR1 (adenosine deaminase acting on RNA1) is an IFN-inducible dsRNA-binding protein with enzyme activity (30, 31). However, unlike PKR, ADAR1 uses dsRNA as a substrate (32). ADAR1 catalyzes the C6 deamination of adenosine (A) in dsRNA structures to generate inosine (I), a process known as A-to-I editing (33,34) samuel@lifesci.ucsb.edu.2 The abbreviations used are: SG, stress granule; ADAR1, adenosine deaminase acting on RNA1; MEF, mouse embryo fibroblast; mmPCR-seq, microfluidics-based multiplex PCR and deep sequencing;...

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STAT2-dependent induction of RNA adenosine deaminase ADAR1 by type I interferon differs between mouse and human cells in the requirement for STAT1

Cited by 22 publications

References 52 publications

Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation

Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation

ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

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