Induction of stress granules by interferon and down-regulation by the cellular RNA adenosine deaminase ADAR1

John, Lijo; Samuel, Charles E.

doi:10.1016/j.virol.2014.02.025

Cited by 26 publications

(29 citation statements)

References 66 publications

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“…Both mouse and human cells deficient in ADAR1 protein display selective marker induction following IFN treatment, including stress granule formation and PKR-dependent phosphorylation. This suggests a universal response to ADAR1 deficiency, illustrated phenotypically by the genetic knock-out of ADAR1 in mouse MEF cells described herein and the short hairpin RNA knockdown of ADAR1 in human HeLa cells (43).…”

Section: Discussionmentioning

confidence: 68%

“…Because the formation of cytoplasmic SG is impaired by ADAR1 both in uninfected IFN-treated mouse MEFs as shown herein (Figs. 1 and 2) and in untreated and IFN-treated HeLa cells following infection (7,43), and because SG formation is PKR-dependent (6, 7) and the IFN-induced phosphorylation of eIF2␣ likewise is PKR-dependent (Fig. 3), it appears that in uninfected ADAR1 p150-deficient cells there is a population of FIGURE 6.…”

Section: Discussionmentioning

confidence: 97%

“…Unexpectedly, IFN treatment of HeLa cells deficient in ADAR1 also was found to cause formation of SG even in the absence of infection, reaching SG levels approaching that seen in measles virus-infected cells (43). ADAR1 is one of the two known catalytically active mammalian A-to-I RNAediting enzymes.…”

Section: Interferon Treatment Leads To Stress Granule Formation Inmentioning

confidence: 95%

“…Conversely, ADAR1 sufficiency correlates with increased virus growth, impaired SG responses, impaired IFN␤ induction, and reduced cytotoxicity and apoptotsis (7,25,27,42). Furthermore, in the absence of virus infection, IFN␤ treatment alone induces SG formation in HeLa cells stably deficient in both p110 and p150 but not in ADAR1 sufficient cells (43). We therefore wanted to test whether IFN treatment in the absence of infection affected the SG response in cells genetically null for a single ADAR gene product and, if so, to assess the effect of IFN treatment on both the global A-to-I RNA editing profile and on PKR activation measured by eIF2␣ phosphorylation.…”

mentioning

confidence: 99%

“…Western Immunoblot Analysis-Western blotting was carried out, as described previously (27,43), using whole-cell extracts (48). Primary antibodies used were as follows: rabbit monoclonal anti-ADAR1 (Santa Cruz Biotechnology, catalog no.…”

mentioning

confidence: 99%

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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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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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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 97%

Section: Interferon Treatment Leads To Stress Granule Formation Inmentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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128

105

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Intrinsic factors behind long COVID: IV. Hypothetical roles of the SARS‐CoV‐2 nucleocapsid protein and its liquid–liquid phase separation

Eltayeb,

Al‐Sarraj,

Alharbi

et al. 2024

J of Cellular Biochemistry

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When the SARS‐CoV‐2 virus infects humans, it leads to a condition called COVID‐19 that has a wide spectrum of clinical manifestations, from no symptoms to acute respiratory distress syndrome. The virus initiates damage by attaching to the ACE‐2 protein on the surface of endothelial cells that line the blood vessels and using these cells as hosts for replication. Reactive oxygen species levels are increased during viral replication, which leads to oxidative stress. About three‐fifths (~60%) of the people who get infected with the virus eradicate it from their body after 28 days and recover their normal activity. However, a large fraction (~40%) of the people who are infected with the virus suffer from various symptoms (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, and tachycardia) beyond 12 weeks and are diagnosed with a syndrome called long COVID. Long‐term clinical studies in a group of people who contracted SARS‐CoV‐2 have been contrasted with a noninfected matched group of people. A subset of infected people can be distinguished by a set of cytokine markers to have persistent, low‐grade inflammation and often self‐report two or more bothersome symptoms. No medication can alleviate their symptoms efficiently. Coronavirus nucleocapsid proteins have been investigated extensively as potential drug targets due to their key roles in virus replication, among which is their ability to bind their respective genomic RNAs for incorporation into emerging virions. This review highlights basic studies of the nucleocapsid protein and its ability to undergo liquid–liquid phase separation. We hypothesize that this ability of the nucleocapsid protein for phase separation may contribute to long COVID. This hypothesis unlocks new investigation angles and could potentially open novel avenues for a better understanding of long COVID and treating this condition.

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Innate Immunity in Viral Encephalitis

Reiss

2016

Neurotropic Viral Infections

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Induction of stress granules by interferon and down-regulation by the cellular RNA adenosine deaminase ADAR1

Cited by 26 publications

References 66 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

Intrinsic factors behind long COVID: IV. Hypothetical roles of the SARS‐CoV‐2 nucleocapsid protein and its liquid–liquid phase separation

Innate Immunity in Viral Encephalitis

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