Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E

Herdy, Barbara; Jaramillo, Maritza; Svitkin, Yuri V.; Rosenfeld, Amy; Kobayashi, Mariko; Walsh, Derek; Alain, Tommy; Sean, Polen; Robichaud, Nathaniel; Topisirović, Ivan; Furic, Luc; Dowling, Ryan J.O.; Sylvestre, Annie; Liang, Rong; Colina, Rodney; Costa-Mattioli, Mauro; Fritz, Jörg H.; Olivier, Martin; Brown, Earl G.; Mohr, Ian; Sonenberg, Nahum

doi:10.1038/ni.2291

Cited by 113 publications

(127 citation statements)

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“…The mechanism for this mode of regulation may involve phosphorylation of the AU-rich element (ARE) binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) by MNK1. Alternatively, eIF4E phosphorylation by MNK1 could differentially translate select mRNAs through their 3= UTR by an unknown mechanism (84,85). As altering MNK1 kinase activity globally decreases lytic replication, it remains to be determined if either of these MNK1 effects applies directly to KSHV 3= UTRs.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Mapping and Analysis of Kaposi's Sarcoma-Associated Herpesvirus 3′ UTRs Identify Differential Posttranscriptional Control of Gene Expression in Lytic versus Latent Infection

McClure

Kincaid

Grundhoff

et al. 2013

J Virol

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b 3= untranslated regions (UTRs) are known to play an important role in posttranscriptional regulation of gene expression. Here we map the 3= UTRs of Kaposi's sarcoma-associated herpesvirus (KSHV) using next-generation RNA sequencing, 3= rapid amplification of cDNA ends (RACE), and tiled microarray analyses. Chimeric reporters containing the KSHV 3= UTRs show a general trend toward reduced gene expression under conditions of latent infection. Those 3= UTRs with a higher GC content are more likely to be associated with reduced gene expression. KSHV transcripts display an extensive use of shared polyadenylation sites allowing for partially overlapping 3= UTRs and regulatory activities. In addition, a subset of KSHV 3= UTRs is sufficient to convey increased gene expression under conditions of lytic infection. These results suggest a role for viral 3= UTRs in contributing to differential gene expression during latent versus lytic infection. The 3= untranslated regions (UTRs), defined as the portion of an mRNA transcript extending from the stop codon to the polyadenylated tail, are known to play an important role in posttranscriptional regulation of gene expression (1). 3= UTRs can alter transcript stability, subcellular localization, and translation efficiency (2-5). Recent studies have demonstrated global alterations in host transcript 3= UTR compositions under different biological conditions related to cell growth and transformation (6, 7). These findings imply a possible role for 3= UTRs expressed by tumor viruses during infection.Although well studied in some RNA viruses (8), the role of viral 3= UTRs remains understudied in DNA viruses. KSHV is a large, double-stranded DNA virus associated with various hyperproliferative disorders, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease (9, 10). Like all herpesviruses, KSHV is characterized by a long-term latent infection, during which the virus effectively evades the host immune system. KSHV harbors approximately 85 well-established protein-encoding genes, at least 5 of which are expressed during latent infection (9, 11). A temporal cascade of gene expression occurs during lytic infection that culminates with the production and dissemination of virions (12-14). To date, only 38 of the ϳ85 KSHV genes have a published, experimentally determined 3= UTR. To our knowledge, no studies have yet examined differences in composition or changes in regulatory activity of DNA virus 3= UTRs in latent (persistent) infection versus lytic (productive) infection.Here, using high-throughput RNA deep sequencing (RNAseq) analysis, we map a majority of the predominant 3= UTRs from most of the known mRNA transcripts (n ϭ 84). We confirmed the accuracy of 66 of these 3= UTRs using traditional rapid amplification of cDNA ends (RACE) analysis and of 5 additional 3= UTRs using tiled microarray analysis. Furthermore, using chimeric reporter assays, we tested their functionality in different cellular contexts. This work unveils a likely role for some KS...

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Section: Discussionmentioning

confidence: 99%

Comprehensive Mapping and Analysis of Kaposi's Sarcoma-Associated Herpesvirus 3′ UTRs Identify Differential Posttranscriptional Control of Gene Expression in Lytic versus Latent Infection

McClure

Kincaid

Grundhoff

et al. 2013

J Virol

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“…Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of eIF4E at S209 (13). Mutation of S209 of eIF4E to alanine suppresses the translation of IκBα mRNA and enhances the transcription activity of NF-κB, which promotes the production of inflammatory cytokines (13). These studies highlight the importance of Mnk1/2-eIF4E-mediated translation control in the innate immune response.…”

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confidence: 98%

“…The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11,12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of eIF4E at S209 (13). Mutation of S209 of eIF4E to alanine suppresses the translation of IκBα mRNA and enhances the transcription activity of NF-κB, which promotes the production of inflammatory cytokines (13).…”

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confidence: 99%

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

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

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Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/ threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.T he inducible transcription factor NF-κB plays a key role in regulating the inflammatory and immune responses in mammals (1, 2). The prototypical NF-κB complex, the heterodimer of p50 and RelA, is sequestered in the cytoplasm by its assembly with its inhibitor IκBα (1, 2). Upon stimulation, IκB kinase complex is activated and phosphorylates IκBα, leading to the degradation of IκBα, the nuclear translocation of NF-κB complex, and the activation of NF-κB target genes (1-3). Importantly, one of NF-κB target genes is its inhibitor, IκBα. The resynthesized IκBα enters the nucleus, where it removes the NF-κB from the DNA and terminates activated NF-κB (1, 2, 4). The resynthesis of IκBα therefore creates a negative feedback regulation of NF-κB signaling, preventing sustained NF-κB activation and prolonged inflammatory response.In addition to the negative feedback regulation from resynthesized IκBα, the NF-κB-mediated inflammatory response is subjected to many layers of regulation, including transcriptional, translational, and posttranslational regulation (5-8). Recent studies demonstrate that selective translational control of gene expression plays an important regulatory role in the inflammatory response (7, 9). The eukaryotic translation initiation factor eIF4E has been shown to be the node of the translational control of immune response via the mTOR signaling pathway or the MAPK-Mnk1-Mnk2-eIF4E pathway (9). Upon LPS stimulation, eIF4E can be activated via its phosphorylation at S209 by Mnk1/2 (10). The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11, 12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of e...

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“…8,9 Type I IFN expression is tightly controlled by multiple intracellular regulators to prevent the development of immunopathological conditions. [10][11][12] Viruses have also developed several strategies to subvert the host immune response to ensure their survival in infected cells. Disruption of host recognition and subsequent impairment of type I IFN production is one of the well-known evading strategies used by viruses.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-466l inhibits antiviral innate immune response by targeting interferon-alpha

Fan

et al. 2012

Cell Mol Immunol

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Effective recognition of viral infections and subsequent triggering of antiviral innate immune responses are essential for the host antiviral defense, which is tightly regulated by multiple regulators, including microRNAs (miRNAs). A previous study showed that miR-466l upregulates IL-10 expression in macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. However, the ability of miR-466l to regulate antiviral immune responses remains unknown. Here, we found that interferon-alpha (IFN-a) expression was repressed in Sendai virus (SeV)-and vesicular stomatitis virus (VSV)-infected macrophages and in dendritic cells transfected with miR-466l expression. Moreover, multiple IFN-a species can be directly targeted by miR-466l through their 39 untranslated region (39UTR). This study has demonstrated that miR-466l could directly target IFN-a expression to inhibit host antiviral innate immune response.

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Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E

Cited by 113 publications

References 50 publications

Comprehensive Mapping and Analysis of Kaposi's Sarcoma-Associated Herpesvirus 3′ UTRs Identify Differential Posttranscriptional Control of Gene Expression in Lytic versus Latent Infection

Comprehensive Mapping and Analysis of Kaposi's Sarcoma-Associated Herpesvirus 3′ UTRs Identify Differential Posttranscriptional Control of Gene Expression in Lytic versus Latent Infection

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

MicroRNA-466l inhibits antiviral innate immune response by targeting interferon-alpha

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