mRNA Decay Factor AUF1 Binds the Internal Ribosomal Entry Site of Enterovirus 71 and Inhibits Virus Replication

Lin, Jing; Li, Meiling; Brewer, Gary

doi:10.1371/journal.pone.0103827

Cited by 39 publications

(100 citation statements)

References 46 publications

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“…By binding to defined genomic elements and by modulating viral protein or RNA synthesis, AUF1/hnRNPD was found to accelerate or inhibit the life cycles of various RNA viruses (Paek et al 2008;Lund et al 2012;Cathcart et al 2013;Hino et al 2013;Lin et al 2014). It is quite conceivable that the methylation-enhanced RNA restructuring activity of the AUF1 p45 isoform, which was demonstrated here to support WNV replication, may underlie several of the functions of AUF1 during the replication processes of other viruses as well.…”

Section: Discussionmentioning

confidence: 67%

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Friedrich

Schmidt

Schierhorn

et al. 2016

RNA

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A prerequisite for the intracellular replication process of the Flavivirus West Nile virus (WNV) is the cyclization of the viral RNA genome, which enables the viral replicase to initiate RNA synthesis. Our earlier studies indicated that the p45 isoform of the cellular AU-rich element binding protein 1 (AUF1) has an RNA chaperone activity, which supports RNA cyclization and viral RNA synthesis by destabilizing a stem structure at the WNV RNA's 3 ′ -end. Here we show that in mammalian cells, AUF1 p45 is consistently modified by arginine methylation of its C terminus. By a combination of different experimental approaches, we can demonstrate that the methyltransferase PRMT1 is necessary and sufficient for AUF1 p45 methylation and that PRMT1 is required for efficient WNV replication. Interestingly, in comparison to the nonmethylated AUF1 p45, the methylated AUF1 p45 aDMA exhibits a significantly increased affinity to the WNV RNA termini. Further data also revealed that the RNA chaperone activity of AUF1 p45 aDMA is improved and the methylated protein stimulates viral RNA synthesis considerably more efficiently than the nonmethylated AUF1 p45. In addition to its destabilizing RNA chaperone activity, we identified an RNA annealing activity of AUF1 p45, which is not affected by methylation. Arginine methylation of AUF1 p45 thus represents a specific determinant of its RNA chaperone activity while functioning as a WNV host factor. Our data suggest that the methylation modifies the conformation of AUF1 p45 and in this way affects its RNA binding and restructuring activities.

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Section: Discussionmentioning

confidence: 67%

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Friedrich

Schmidt

Schierhorn

et al. 2016

RNA

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“…Among them, several members of the hnRNPs family have been previously shown to play a role in regulating viral replication. 7,8,39,[44][45][46][47] For examples, hnRNP C and K were documented to interact with the non-coding regions of enteroviral RNA to facilitate translation initiation and RNA synthesis. 44,45,47 Similar to our findings in the current study, enteroviral infection causes cytoplasmic redistribution and cleavage of hnRNP D and deletion of this protein results in enhanced viral replication, suggesting that hnRNA D acts as a host restriction factor against enterovirus infection.…”

Section: Discussionmentioning

confidence: 99%

“…44,45,47 Similar to our findings in the current study, enteroviral infection causes cytoplasmic redistribution and cleavage of hnRNP D and deletion of this protein results in enhanced viral replication, suggesting that hnRNA D acts as a host restriction factor against enterovirus infection. 7,8,39 The antiviral mechanisms of hnRNP D appear to involve negative regulation of internal ribosome entry site (IRES)-mediated translation of viral RNA via direct interaction with the IRES of enteroviruses, 7,46 and viral RNA degradation by targeting the 3′-untranslated region (UTR) of enteroviral genome. 39 The exact mechanism of TDP-43 suppressing CVB3 replication remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

et al. 2015

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We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin-protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at aminoacid 327 between glutamine and alanine, resulting in the generation of an N-and C-terminal cleavage fragment of~35 and~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection. Coxsackievirus B3 (CVB3) is a small, positive-stranded RNA enterovirus. 1 The single open reading frame of CVB3 is translated into a viral polypeptide that is subsequently cleaved by two virus-encoded proteases 2A and 3C to generate structural and non-structural proteins. 2 In addition to processing viral polyprotein, 2A and 3C target host proteins important for maintenance of protein translation and transcription, antiviral activity, and cellular architecture and signaling, contributing to virus-induced pathogenesis. [3][4][5] Although enteroviral replication takes place exclusively in the cytoplasm, viral infection has been demonstrated to lead to cytoplasmic translocation of nuclear proteins. 6 For example, heterogeneous ribonucleoprotein D (hnRNP D) has been shown to translocate from the nucleus to the cytoplasm during enteroviral infection. 5,7,8 Moreover, hnRNP D is cleaved by 3C and has an antiviral function against enteroviral infection. 5,7,8 Cytoplasmic translocation after enteroviral infection has also been demonstrated for several other hnRNPs (A1, C, and K)...

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“…Pairing PAR-CLIP with RNA-seq and polysome analysis following AUF1 overexpression implicated AUF1 in a range of regulatory events including stabilization and destabilization of both mRNA and ncRNA, promotion and repression of translation, and modulation of alternative splicing. In addition, AUF1 has recently been shown to have a role in the life cycle of DNA and RNA viruses including Epstein-Barr virus [123,124], HIV [125], hepatitis C virus [126], West Nile virus [127,128], and several picornaviruses [129,130,131,132]. …”

Section: Adenylate Uridylate-rich Element (Are)-mediated Mrna Decamentioning

confidence: 99%

“…This finding was later expanded to include binding to HRV, CVB3, and EV71 RNA [129,132,133]. It was subsequently discovered that AUF1 knockout or knockdown in human or mouse cells resulted in increased replication of these viruses, suggesting that AUF1 may act as a host restriction factor to EV infection [129,130,131,132]. Prior to these discoveries, a study of HRV-16 infection of human airway epithelial cells reported the observation that cytoplasmic levels of AUF1 increased during infection [134].…”

Section: Adenylate Uridylate-rich Element (Are)-mediated Mrna Decamentioning

confidence: 99%

Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways

Ullmer

Semler

2016

Viruses

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To successfully replicate, viruses protect their genomic material from degradation by the host cell. RNA viruses must contend with numerous destabilizing host cell processes including mRNA decay pathways and viral RNA (vRNA) degradation resulting from the antiviral response. Members of the Picornaviridae family of small RNA viruses have evolved numerous diverse strategies to evade RNA decay, including incorporation of stabilizing elements into vRNA and re-purposing host stability factors. Viral proteins are deployed to disrupt and inhibit components of the decay machinery and to redirect decay machinery to the advantage of the virus. This review summarizes documented interactions of picornaviruses with cellular RNA decay pathways and processes.

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mRNA Decay Factor AUF1 Binds the Internal Ribosomal Entry Site of Enterovirus 71 and Inhibits Virus Replication

Cited by 39 publications

References 46 publications

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways

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