The RNA‐binding protein HuR/ELAVL1 regulates IFN‐β mRNA abundance and the type I IFN response

Herdy, Barbara; Karonitsch, Thomas; Vladimer, Gregory I.; Tan, Chris Soon Heng; Stukalov, Alexey; Trefzer, Claudia; Bigenzahn, Johannes W.; Theil, Tamara; Holinka, Johannes; Kiener, Hans P.; Colinge, Jacques; Bennett, Keiryn L.; Superti‐Furga, Giulio

doi:10.1002/eji.201444979

Cited by 52 publications

(45 citation statements)

References 64 publications

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“…The IFN-β 3′ UTR contains a highly conserved ARE (63, 64), which has been shown to promote deadenylation of the IFN-β mRNA (63). Although TTP has not yet been directly implicated in regulating IFN-β expression, the ARE contains a perfect match to the consensus TTP binding site, UAUUUAU, and two additional, closely related sequences (62). Recent studies have used cross-linking and immunoprecipitation to identify transcriptome-wide targets of TTP (74, 75).…”

Section: Discussionmentioning

confidence: 99%

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

McGuire

Rosner

Ananieva

et al. 2017

Molecular and Cellular Biology

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Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNK-mediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.

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Section: Discussionmentioning

confidence: 99%

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

McGuire

Rosner

Ananieva

et al. 2017

Molecular and Cellular Biology

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“…IL-6 mRNA is stabilized and degraded by AT-rich interactive domain-containing protein 5A and Regnase-1, respectively [40, 41]. IFN-β mRNA is stabilized by HuR protein, which binds to A/U-rich elements on 3′ untranslated regions [18, 42]. Prokunia-Olsson et al reported that IFN-λ mRNA was still detectable 24 h after poly I:C stimulation [43].…”

Section: Discussionmentioning

confidence: 99%

Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production

et al. 2016

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Stress granules (SGs) are cytoplasmic granular aggregations that are induced by cellular stress, including viral infection. SGs have opposing antiviral and proviral roles, which depend on virus species. The exact function of SGs during viral infection is not fully understood. Here, we showed that mumps virus (MuV) induced SGs depending on activation of protein kinase R (PKR). MuV infection strongly induced interferon (IFN)-λ1, 2 and 3, and IFN-β through activation of IFN regulatory factor 3 (IRF3) via retinoic acid inducible gene-I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. MuV-induced IFNs were strongly upregulated in PKR-knockdown cells. MuV-induced SG formation was suppressed by knockdown of PKR and SG marker proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and T-cell-restricted intracellular antigen-1, and significantly increased the levels of MuV-induced IFN-λ1. However, viral titer was not altered by suppression of SG formation. PKR was required for induction of SGs by MuV infection and regulated type III IFN (IFN-λ1) mRNA stability. MuV-induced SGs partly suppressed type III IFN production by MuV; however, the limited suppression was not sufficient to inhibit MuV replication in cell culture. Our results provide insight into the relationship between SGs and IFN production induced by MuV infection.

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“…ELAVL1 (also known as HUR) is a RBP known to bind to AU-rich elements (AREs) (Herdy et al 2015). An interesting aspect of ELAVL1 is that it preferentially binds mRNAs that lack N 6 -methyladenosine (m 6 A) sites, stabilizing targeted mRNAs .…”

Section: Identification Of Previously Unrecognized Ribosomal Rbpsmentioning

confidence: 99%

Specific RNP capture with antisense LNA/DNA mixmers

Rogell

Fischer

Rettel

et al. 2017

RNA

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RNA-binding proteins (RBPs) play essential roles in RNA biology, responding to cellular and environmental stimuli to regulate gene expression. Important advances have helped to determine the (near) complete repertoires of cellular RBPs. However, identification of RBPs associated with specific transcripts remains a challenge. Here, we describe "specific ribonucleoprotein (RNP) capture," a versatile method for the determination of the proteins bound to specific transcripts in vitro and in cellular systems. Specific RNP capture uses UV irradiation to covalently stabilize protein-RNA interactions taking place at "zero distance." Proteins bound to the target RNA are captured by hybridization with antisense locked nucleic acid (LNA)/DNA oligonucleotides covalently coupled to a magnetic resin. After stringent washing, interacting proteins are identified by quantitative mass spectrometry. Applied to in vitro extracts, specific RNP capture identifies the RBPs bound to a reporter mRNA containing the Sex-lethal (Sxl) binding motifs, revealing that the Sxl homolog sister of Sex lethal (Ssx) displays similar binding preferences. This method also revealed the repertoire of RBPs binding to 18S or 28S rRNAs in HeLa cells, including previously unknown rRNA-binding proteins.

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The RNA‐binding protein HuR/ELAVL1 regulates IFN‐β mRNA abundance and the type I IFN response

Abstract: Secretion of type I interferon (IFN) isAdditional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 52 publications

References 64 publications

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production

Specific RNP capture with antisense LNA/DNA mixmers

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