Activation of the RNA-dependent Protein Kinase PKR Promoter in the Absence of Interferon Is Dependent Upon Sp Proteins

Das, Sonali; Ward, Simone Visosky; Tacke, Robert; Suske, Guntram; Samuel, Charles E.

doi:10.1074/jbc.m510612200

Cited by 37 publications

(31 citation statements)

References 55 publications

(124 reference statements)

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“…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). IFN treatment increased PKR protein levels in both ADAR1-deficient (Adar1 Ϫ/Ϫ ) and ADAR1-sufficient (WT, Adar2 Ϫ/Ϫ ) MEFs; however, the IFN treatment led to an increased eIF2␣ phosphorylation and SG formation only in the Adar1 Ϫ/Ϫ cells (Figs.…”

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

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123

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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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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

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123

101

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“…Thus, in the context of rotavirus activation of the innate immune response, PKR is critical for the secretory phase but not for the early PRR-mediated transcriptional phase, which is dependent instead on MAVS, RIG-I/MDA-5, and IRF3. Mammalian PKR is an IFN-inducible Ser/Thr kinase though it is also basally expressed in MEFs and is associated with ribosomes in an unphosphorylated state (12,59). In the context of PKR as a protein synthesis inhibitor, the activation of PKR by dsRNA leads to inhibitory Ser51 phosphorylation of the translation initiation factor eIF2␣ (14).…”

Section: Discussionmentioning

confidence: 99%

The Early Interferon Response to Rotavirus Is Regulated by PKR and Depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3

Pruijssers

Dermody

et al. 2011

J Virol

134

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In mouse embryonic fibroblasts (MEFs), the bovine rotavirus (UK strain) but not the simian rhesus rotavirus (RRV) robustly triggers beta interferon (IFN-␤Rotaviruses are etiological agents of severe dehydrating diarrhea in infants and young children and cause nearly 600,000 deaths globally every year (34). Rotaviruses are nonenveloped icosahedral members of the family Reoviridae and contain 11 segments of genomic double-stranded RNA (dsRNA) within a triple-layered particle. Several rotavirus vaccines have been developed to reduce rotavirus-associated mortalities (26); some are based on a modified Jennerian principle of rotavirus attenuation in the heterologous host. This phenomenon is termed host range restriction and is manifested by poor replication of rotaviruses in heterologous hosts compared to that in the homologous host (1). For example, bovine, lapine, and simian rotaviruses are all restricted for replication in humans. We are interested in understanding the mechanisms underlying host range restriction of rotaviruses in order to improve our basic knowledge of viral pathogenesis and because of the importance of these mechanisms in rational attenuation of vaccine candidates.In primary mouse embryonic fibroblasts (MEFs), several heterologous (nonmurine) rotavirus strains, including the bovine UK strain, are replication restricted by the host type I interferon (IFN) response (17, 53). In contrast, replication of homologous murine EW virus and the heterologous simian rhesus rotavirus (RRV) strain is insensitive to the presence of the interferon system. In a mouse model of rotavirus infection, RRV replication in gallbladder epithelia correlates with its ability to suppress the IFN response (N. Feng et al., submitted for publication). The rotavirus gene segment encoding the nonstructural protein 1 (NSP1) is an important determinant of host restriction of viral replication both in vitro (17,53) and in vivo (9). Specifically, we along with others have reported a role for NSP1 in regulating the ability of rotavirus to efficiently cause diarrhea in mice (9), spread from animal to animal (9), replicate in vivo and in vitro (4,(15)(16)(17), and antagonize IFN (4,5,17,24,25,53). Thus, the host innate immune response is an important determinant of rotavirus host range restriction and depends on both the virus strain and host cell or tissue type.Mammalian innate immunity to viral infection is critically dependent on a successful type I IFN response (49). The early IFN response involves initial recognition of virus within infected cells by activation of host pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs)

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“…Western Blot Analyses-Whole cell extracts were prepared with buffer containing protease inhibitors as previously described (39); for measurement of eIF-2␣ and PKR phosphorylation, 50 nM NaF and 2 nM Na 2 VO 3 (31) or commercial phosphatase inhibitors (Sigma) were also present. Protein fractionation and immunoblot analysis were as described (27,40) using the following primary antibodies: PKR and IB-␣ (Santa Cruz Biotechnology); phosphorylated-PKR threonine 446 (Epitomics); eIF-2␣ (Cell Signaling Technology) and phosphorylatedeIF-2␣ serine 51 (Cell Signaling Technology or Epitomics) and ␣-tubulin (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Protein Kinase PKR Amplification of Interferon β Induction Occurs through Initiation Factor eIF-2α-mediated Translational Control

McAllister

Taghavi

Samuel

2012

Journal of Biological Chemistry

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Background: RNA-dependent protein kinase PKR regulates interferon induction. Results: Knockdown of PKR or mutation of initiation factor eIF-2␣ results in increased IB-␣ protein levels and decreased IFN-␤ induction in RNA-transfected and virus-infected cells. Conclusion: PKR amplifies IFN-␤ induction through an eIF-2␣ translational control response. Significance: PKR functions together with additional RNA sensors to modulate signaling leading to interferon gene induction.

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Activation of the RNA-dependent Protein Kinase PKR Promoter in the Absence of Interferon Is Dependent Upon Sp Proteins

Cited by 37 publications

References 55 publications

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

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

The Early Interferon Response to Rotavirus Is Regulated by PKR and Depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3

Protein Kinase PKR Amplification of Interferon β Induction Occurs through Initiation Factor eIF-2α-mediated Translational Control

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