Dual effects of duplex RNA harboring 5′-terminal triphosphate on gene silencing and RIG-I mediated innate immune response

Baek, Si Eun; Kim, Hyo-Seon; Kim, Kyung Bo; Yoon, Seok-Nam; Choe, Juhui; Suh, Wonhee; Jeong, Young-Keun; Cho, Yo Han; Kim, Dong-Eun

doi:10.1016/j.bbrc.2014.11.119

Cited by 2 publications

(5 citation statements)

References 20 publications

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“…Combined, these data demonstrate that the 5 ′ -phosphate group can strongly influence AGO association with small RNAs via a 5 ′ monophosphate-dependent strand selection mechanism coupled to or enhanced by Dicer and/or Dicer-associated proteins during pre-miRNA processing. Since 5 ′ triphosphorylated shRNAs and siRNAs have technological applications and are potential therapeutic agents (Paddison et al 2002;ter Brake et al 2006;Lin et al 2012;Chen et al 2013b;Baek et al 2015), DUSP11 activity may be a major factor affecting the utility of these approaches.…”

Section: Discussionmentioning

confidence: 99%

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

et al. 2016

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RNA silencing is a conserved eukaryotic gene expression regulatory mechanism mediated by small RNAs. In Caenorhabditis elegans, the accumulation of a distinct class of siRNAs synthesized by an RNA-dependent RNA polymerase (RdRP) requires the PIR-1 phosphatase. However, the function of PIR-1 in RNAi has remained unclear. Since mammals lack an analogous siRNA biogenesis pathway, an RNA silencing role for the mammalian PIR-1 homolog (dual specificity phosphatase 11 [DUSP11]) was unexpected. Here, we show that the RNA triphosphatase activity of DUSP11 promotes the RNA silencing activity of viral microRNAs (miRNAs) derived from RNA polymerase III (RNAP III) transcribed precursors. Our results demonstrate that DUSP11 converts the 5 ′ triphosphate of miRNA precursors to a 5 ′ monophosphate, promoting loading of derivative 5p miRNAs into Argonaute proteins via a Dicer-coupled 5 ′ monophosphate-dependent strand selection mechanism. This mechanistic insight supports a likely shared function for PIR-1 in C. elegans. Furthermore, we show that DUSP11 modulates the 5 ′ end phosphate group and/or steady-state level of several host RNAP III transcripts, including vault RNAs and Alu transcripts. This study shows that steady-state levels of select noncoding RNAs are regulated by DUSP11 and defines a previously unknown portal for small RNA-mediated silencing in mammals, revealing that DUSP11-dependent RNA silencing activities are shared among diverse metazoans.

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Section: Discussionmentioning

confidence: 99%

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

et al. 2016

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“…3). Previously, we observed that RNAs containing the 5'-ppp moiety significantly increased the expression of type I IFN compared with their RNA counterparts without the 5'-ppp moiety in A549 cells through a RIG-I-mediated innate immune response (7). In addition, it has been recently reported that the presence of 5'-triphosphate in duplex RNA facilitate conformational change of RIG-I to form dimers by exposing CARD domain through interaction with positively charged residues of RIG-I such as lysine or histidine, which can stimulate IFN-β induction pathway in cells.…”

Section: Resultsmentioning

confidence: 99%

“…RIG-I belongs to the DExD/H family of helicases, which are characterized by both nucleic acid-binding and ATP hydrolysis activities (456). Activation of RIG-I by the binding of exogenous RNA present in the cytoplasm invokes antiviral responses including type I interferon (IFN) expression, inflammasome activation, and proapoptotic signaling (17). …”

Section: Introductionmentioning

confidence: 99%

“…Several reports have shown that C-terminal RDs recognize distinct RNA patterns such as single-stranded (ss) or double-stranded RNA (dsRNA) ends containing either 5'-triphosphate (5'-ppp) or 5'-diphosphate (5'-pp) moieties (789). These patterns are viral RNA signature motifs and are believed to be related to the extent of the type I IFN immune response in cells (8).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, our group demonstrated that RIG-I favors 5'-ppp RNA ligands over RNA ligands that lack the 5'-ppp moiety (i.e., HO-RNA), and the 5'-ppp moiety of RNA strands invokes elevated induction of type I IFN in cells that express RIG-I (7). However, apart from the RNA-binding activities of RIG-I the exact roles of ATP-binding and hydrolysis in activating RIG-I for immune signaling have not been clearly defined.…”

Section: Introductionmentioning

confidence: 99%

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Dependence of RIG-I Nucleic Acid-Binding and ATP Hydrolysis on Activation of Type I Interferon Response

et al. 2016

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Exogenous nucleic acids induce an innate immune response in mammalian host cells through activation of the retinoic acid-inducible gene I (RIG-I). We evaluated RIG-I protein for RNA binding and ATPase stimulation with RNA ligands to investigate the correlation with the extent of immune response through RIG-I activation in cells. RIG-I protein favored blunt-ended, double-stranded RNA (dsRNA) ligands over sticky-ended dsRNA. Moreover, the presence of the 5'-triphosphate (5'-ppp) moiety in dsRNA further enhanced binding affinity to RIG-I. Two structural motifs in RNA, blunt ends in dsRNA and 5'-ppp, stimulated the ATP hydrolysis activity of RIG-I. These structural motifs also strongly induced IFN expression as an innate immune response in cells. Therefore, we suggest that IFN induction through RIG-I activation is mainly determined by structural motifs in dsRNA that increase its affinity for RIG-I protein and stimulate ATPase activity in RIG-I.

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Dual effects of duplex RNA harboring 5′-terminal triphosphate on gene silencing and RIG-I mediated innate immune response

Cited by 2 publications

References 20 publications

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

Dependence of RIG-I Nucleic Acid-Binding and ATP Hydrolysis on Activation of Type I Interferon Response

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