RNA Granule Assembly and Disassembly Modulated by Nuclear Factor Associated with Double-stranded RNA 2 and Nuclear Factor 45

Shiina, Nobuyuki; Nakayama, Kei Ichi

doi:10.1074/jbc.m114.556365

Cited by 26 publications

(29 citation statements)

References 62 publications

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“…As expected, the poly(I:C)-stimulation-caused circRNA reduction could be noticeably rescued by overexpression of NF90 for examined circRNAs ( Figure 4I). Furthermore, it has been shown that the NF90/NF110 export depends on PKR activation and phosphorylation upon infection (Harashima et al, 2010;Shiina and Nakayama, 2014). Consistent with these studies, we found that NF90/NF110 were no longer exported to the cytoplasm upon poly(I:C) treatment ( Figure S6A, middle and right panels) in PKR-depleted cells ( Figure S6D).…”

Section: Nf90/nf110 Promote Circrna Processing By Stabilizing Flankinsupporting

confidence: 90%

Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection

et al. 2017

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Circular RNAs (circRNAs) generated via back-splicing are enhanced by flanking complementary sequences. Expression levels of circRNAs vary under different conditions, suggesting participation of protein factors in their biogenesis. Using genome-wide siRNA screening that targets all human unique genes and an efficient circRNA expression reporter, we identify double-stranded RNA-binding domain containing immune factors NF90/NF110 as key regulators in circRNA biogenesis. NF90/NF110 promote circRNA production in the nucleus by associating with intronic RNA pairs juxtaposing the circRNA-forming exon(s); they also interact with mature circRNAs in the cytoplasm. Upon viral infection, circRNA expression is decreased, in part owing to the nuclear export of NF90/NF110 to the cytoplasm. Meanwhile, NF90/NF110 released from circRNP complexes bind to viral mRNAs as part of their functions in antiviral immune response. Our results therefore implicate a coordinated regulation of circRNA biogenesis and function by NF90/NF110 in viral infection.

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Section: Nf90/nf110 Promote Circrna Processing By Stabilizing Flankinsupporting

confidence: 90%

Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection

et al. 2017

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“…Directly or not, members of the Ilf3 family are involved in all steps of RNA metabolism from transcription to degradation. In addition to the above described functions, mouse Ilf3, but not NF90, was very recently reported to promote the assembly of RNA granules, messenger RNP (mRNP) complexes that regulate mRNA translation and cytosolic localization, whereas NF45 was found to enhance their disassembly in Xenopus cells. Ilf3 association with mRNP complexes requires its specific C‐terminal domain and its promoting assembly activity is regulated by interaction with NF45 as well as by phosphorylation at PKR sites localized in the domain associated with zinc fingers .…”

Section: Resultsmentioning

confidence: 99%

Ilf3 and NF90 functions in RNA biology

et al. 2014

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Double-stranded RNA-binding proteins (DRBPs) are known to regulate many processes of RNA metabolism due, among others, to the presence of double-stranded RNA (dsRNA)-binding motifs (dsRBMs). Among these DRBPs, Interleukin enhancer-binding factor 3 (Ilf3) and Nuclear Factor 90 (NF90) are two ubiquitous proteins generated by mutually exclusive and alternative splicings of the Ilf3 gene. They share common N-terminal and central sequences but display specific C-terminal regions. They present a large heterogeneity generated by several post-transcriptional and post-translational modifications involved in their subcellular localization and biological functions. While Ilf3 and NF90 were first identified as activators of gene expression, they are also implicated in cellular processes unrelated to RNA metabolism such as regulation of the cell cycle or of enzymatic activites. The implication of Ilf3 and NF90 in RNA biology will be discussed with a focus on eukaryote transcription and translation regulation, on viral replication and translation as well as on noncoding RNA field.

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“…More work is required to determine if G3BP1 plays only scaffolding/ recruitment roles, can activate PKR alone, or requires a third factor or several other cofactors to activate PKR. Other PKR-interacting proteins have been described that either activate PKR (PACT, IPS1, and NFAR1/2) or inhibit PKR (MDA7, hDUS2, and p58 IPK ) (46)(47)(48)(49)(50)(51)(52). It would be of interest to investigate whether these proteins also interact with G3BP1-induced SGs and modulate SG assembly.…”

Section: Discussionmentioning

confidence: 99%

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Reineke

Lloyd

2015

J Virol

173

189

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Stress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear. Previously, we also showed a link between G3BP1-induced SGs and protein kinase R (PKR)-mediated translational control, but the mechanism of PKR interplay with SG and the antiviral consequences are unknown. Here, we show that G3BP1 exhibits antiviral activity against several enteroviruses, whereas truncated G3BP1 that cannot form SGs does not. G3BP1-induced SGs are linked to activation of innate immune transcriptional responses through NF-B and JNK. The G3BP1-induced SGs also recruit PKR and other antiviral proteins. We show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to SGs, for eIF2␣ phosphorylation driven by PKR, and for nucleating SGs of normal composition. We also show that deletion of the PXXP domain in G3BP1 compromises its antiviral activity. These findings tie PKR activation to its recruitment to SGs by G3BP1 and indicate that G3BP1 promotes innate immune responses at both the transcriptional and translational levels and integrates cellular stress responses and innate immunity. IMPORTANCEStress granules appear during virus infection, and their importance is not well understood. Previously, it was assumed that they were nonfunctional artifacts associated with cellular stress. PKR is a well-known antiviral protein; however, its regulation in cells is not well understood. Our work links cellular stress granules with activation of PKR and other innate immune pathways through the activity of G3BP1, a critical stress granule component. The ability of stress granules and G3BP1 to activate PKR and other innate immune transcriptional responses indicates that G3BP1 is an antiviral protein. This work helps to refine a longstanding paradigm indicating stress granules are inert structures and explains why G3BP1 is subverted by many viruses to promote a productive infection. Stress granules (SGs) are macromolecular triage centers for mRNAs that contain translationally silenced messenger RNPs (mRNPs). Stress granules contain many translation initiation factors, 40S ribosomal subunits, mRNAs, and RNA-binding proteins, which form in response to cellular stresses that inhibit protein synthesis (1, 2). Stress responses are induced during virus infection and are countered by viruses to maximize replication efficiency. Indeed, several examples of viral SG disruption and viral subversion of SG proteins have been described (3-6), indicating stress granules may play antiviral roles against these viruses. Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactiv...

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RNA Granule Assembly and Disassembly Modulated by Nuclear Factor Associated with Double-stranded RNA 2 and Nuclear Factor 45

Cited by 26 publications

References 62 publications

Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection

Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection

Ilf3 and NF90 functions in RNA biology

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

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