Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response

Pfaller, Christian K.; Li, Zhiqun; George, Cyril X.; Samuel, Charles E.

doi:10.1016/j.coi.2011.08.009

Cited by 128 publications

(127 citation statements)

References 89 publications

(189 reference statements)

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“…Phosphorylation of PKR is essential for activation of its function, and it can be regulated by host RNA-binding proteins other than dsRNA (47)(48)(49). Two models currently describe PKR activation: the autoinhibition and dimerization models (50).…”

Section: /2mentioning

confidence: 99%

NF90 Exerts Antiviral Activity through Regulation of PKR Phosphorylation and Stress Granules in Infected Cells

Wen

Huang

Mok

et al. 2014

The Journal of Immunology

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NF90 was shown to exhibit broad antiviral activity against several viruses, but detailed mechanisms remain unclear. In this study, we examined the molecular basis for the inhibitory effect of NF90 on virus replication mediated through protein kinase (PKR)-associated translational regulation. We first verified the interaction between NF90 and PKR in mammalian cells and showed that NF90 interacts with PKR through its C-terminal and that the interaction is independent of NF90 RNA-binding properties. We further showed that knockdown of NF90 resulted in significantly lower levels of PKR phosphorylation in response to dsRNA induction and influenza virus infection. We also showed that high concentrations of NF90 exhibit negative regulatory effects on PKR phosphorylation, presumably through competition for dsRNA via the C-terminal RNA-binding domain. PKR activation is essential for the formation of stress granules in response to dsRNA induction. Our results showed that NF90 is a component of stress granules. In NF90-knockdown cells, dsRNA treatment induced significantly lower levels of stress granules than in control cells. Further evidence for an NF90–PKR antiviral pathway was obtained using an NS1 mutated influenza A virus specifically attenuated in its ability to inhibit PKR activation. This mutant virus replicated indistinguishably from wild-type virus in NF90-knockdown cells, but not in scrambled control cells or Vero cells, indicating that NF90’s antiviral function occurs through interaction with PKR. Taken together, these results reveal a yet-to-be defined host antiviral mechanism in which NF90 upregulation of PKR phosphorylation restricts virus infection.

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Section: /2mentioning

confidence: 99%

NF90 Exerts Antiviral Activity through Regulation of PKR Phosphorylation and Stress Granules in Infected Cells

Wen

Huang

Mok

et al. 2014

The Journal of Immunology

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“…In contrast to PKR, ADAR1 is typically proviral and antiapoptotic (31,39). The proviral and antiapoptotic activities of ADAR1 have been demonstrated with several viruses, including measles virus, hepatitis delta virus, Venezuelan equine encephalitis virus, yellow fever virus, and HIV (27,31,40,41).…”

mentioning

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

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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“…When intracellular or extracellular viral particles stimulate the body's innate immune response, cells produce interferons and simultaneously upregulate PKR. Double-stranded RNA (dsRNA) elements within the viral genome can induce activation of PKR [4]. Therefore, PKR can be considered as a cellular sensor of viral contamination.…”

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confidence: 99%

Structure of the kinase domain of human RNA-dependent protein kinase with K296R mutation reveals a face-to-face dimer

Wang

et al. 2012

Chin. Sci. Bull.

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RNA-dependent protein kinase (PKR) is crucial for the innate immune response, cell growth, proliferation, signal transduction and apoptosis. The activation process of PKR has been studied for many years and is still under debate. To obtain new insight into the mechanism of PKR activation, we solved the crystal structure of a latent mutant of the PKR kinase domain (PKR-KD) in the apo form at a resolution of 2.9 Å. The overall structure of PKR-KD is similar to previously reported structures. Structural analysis revealed a classical back-to-back dimer and a newly defined face-to-face dimer. Analytical ultracentrifugation experiments, electrostatic surface maps and the model of PKR-KD in complex with the eIF2 substrate all support that the face-to-face dimer is more reflective of PKR in solution. Our results provide new information on PKR dimerization and its activation mechanism. PKR, dimerization, crystal structure, PKR activation Citation:Li F Z, Li S W, Wang Z, et al. Structure of the kinase domain of human RNA-dependent protein kinase with K296R mutation reveals a face-to-face dimer.

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Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response

Cited by 128 publications

References 89 publications

NF90 Exerts Antiviral Activity through Regulation of PKR Phosphorylation and Stress Granules in Infected Cells

NF90 Exerts Antiviral Activity through Regulation of PKR Phosphorylation and Stress Granules in Infected Cells

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

Structure of the kinase domain of human RNA-dependent protein kinase with K296R mutation reveals a face-to-face dimer

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