The Double-Stranded RNA-Binding Protein PACT Functions as a Cellular Activator of RIG-I to Facilitate Innate Antiviral Response

Kok, Kin‐Hang; Lui, Pak-Yin; Ng, Ming-Him James; Siu, Kam‐Leung; Au, Shannon Wing Ngor; Jin, Dong-Yan

doi:10.1016/j.chom.2011.03.007

Cited by 156 publications

(225 citation statements)

References 52 publications

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“…This implication of PACT in endocrine signaling is consistent with its reported role in postnatal anterior pituitary proliferation (25). Our findings add to the repertoire of functions of PACT, which includes the regulation of retinoic-acid-inducible gene 1 expression as part of the antiviral response (26), and ear development and hearing (27).…”

Section: Discussionsupporting

confidence: 74%

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Redfern

Colley

Beveridge

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

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The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression. Furthermore, each of the RISC proteins, together with Argonaute 2, associates with SRA and specific pre-microRNAs in both the nucleus and cytoplasm, providing evidence for links between NR-mediated transcription and some of the factors involved in miRNA processing.noncoding RNA | androgen action | prostate cancer M icroRNAs (miRNAs) are 22-nt noncoding RNAs that regulate gene expression by associating with the multiprotein RNA-induced silencing complex (RISC) and guiding RISC to silence specific mRNA species by mRNA degradation or translational inhibition (1). miRNAs are derived from large primary RNA transcripts, which are processed in the nucleus by Drosha/ Pasha into ∼70-nt precursor (pre-miRNA) duplexes. These duplexes are exported to the cytoplasm, and their conversion to mature 22-nt miRNAs is mediated by a transactivation response (TAR) RNA binding protein (TRBP)-Dicer complex (1), which provides a platform for RISC assembly and aids recruitment of Argonaute 2 (Ago2), the catalytic enzyme of RISC required for miRNA processing (2, 3). Protein kinase RNA (PKR) activator (PACT) is also integral to the RISC complex and associates with Dicer (4). TRBP and PACT are critical for efficient miRNA processing, because their depletion results in decreased mature miRNA levels and target gene silencing (2, 4, 5).Ligand-activated signaling by nuclear receptors (NRs) plays a key role in the promotion of human tumorigenesis. NR coregulators are a group of >300 molecules that act to fine tune ligand-induced gene transcription by acting as either coactivators [e.g., steroid receptor coactivator-1 (SRC-1)] or corepressors [e.g., nuclear receptor corepressor1 (NCoR1)] (6). One of the NR coregulators, steroid receptor RNA activator (SRA), is unique, because its RNA transcript functions to coactivate NR activity (7-9).Several links between miRNA pathways and NR action have been reported. miRNAs can regulate NR signaling at different levels, including targeting NRs [e.g., estrogen receptor-α (ERα)] (10, 11) or NR coregulator transcripts (e.g., amplified in breast cancer 1) (12). Conversely, NRs regulate an array of miRNAs in endocrine tissues (13). For example, ERα can regulate miRNA-21 expression at the transcriptional level (14) and the...

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Section: Discussionsupporting

confidence: 74%

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Redfern

Colley

Beveridge

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Alternatively, rather than being inhibited, the activities of certain components of the RNAi machinery may be redirected to alternate functions in the regulation of IFN induction during viral infection. The dsRNA‐binding protein PACT, for example, is important for optimal miRNA processing by Dicer, but also binds the CTD of RIG‐I and potentiates activation of IFN production through RIG‐I in the context of Sendai virus infection (Kok et al , 2011). A similar observation was made for TRBP, which was found to enhance signalling via MDA5 but not RIG‐I (Komuro et al , 2016), although we failed to substantiate this in our assays.…”

Section: Discussionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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“…Recombinant vesicular stomatitis virus expressing GFP (vesicular stomatitis virus [VSV]-GFP) was a gift from Dr. Jacques Perrault (San Diego State University, San Diego, CA) and Dr. Brian Lichty (McMaster University, ON, Canada) (27,28). Viral infection of HEK293 cells and MEFs was performed as described (29).…”

Section: Methodsmentioning

confidence: 99%

MIP-T3 Is a Negative Regulator of Innate Type I IFN Response

Kok

et al. 2011

The Journal of Immunology

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TNFR-associated factor (TRAF) 3 is an important adaptor that transmits upstream activation signals to protein kinases that phosphorylate transcription factors to induce the production of type I IFNs, the important effectors in innate antiviral immune response. MIP-T3 interacts specifically with TRAF3, but its function in innate IFN response remains unclear. In this study, we demonstrated a negative regulatory role of MIP-T3 in type I IFN production. Overexpression of MIP-T3 inhibited RIG-I-, MDA5-, VISA-, TBK1-, and IKKε-induced transcriptional activity mediated by IFN-stimulated response elements and IFN-β promoter. MIP-T3 interacted with TRAF3 and perturbed in a dose-dependent manner the formation of functional complexes of TRAF3 with VISA, TBK1, IKKε, and IFN regulatory factor 3. Consistent with this finding, retinoic acid-inducible gene I- and TBK1-induced phosphorylation of IFN regulatory factor 3 was significantly diminished when MIP-T3 was overexpressed. Depletion of MIP-T3 facilitated Sendai virus-induced activation of IFN production and attenuated the replication of vesicular stomatitis virus. In addition, MIP-T3 was found to be dissociated from TRAF3 during the course of Sendai virus infection. Our findings suggest that MIP-T3 functions as a negative regulator of innate IFN response by preventing TRAF3 from forming protein complexes with critical downstream transducers and effectors.

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The Double-Stranded RNA-Binding Protein PACT Functions as a Cellular Activator of RIG-I to Facilitate Innate Antiviral Response

Cited by 156 publications

References 52 publications

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

MIP-T3 Is a Negative Regulator of Innate Type I IFN Response

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