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ELAVL1 primarily couples mRNA stability with the 3' UTRs of interferon-stimulated genes.

ABSTRACT: Upon pathogen detection, the innate immune system triggers signaling events leading to upregulation of pro-inflammatory and anti-microbial mRNA transcripts. RNA-binding proteins (RBPs) interact with these critical mRNAs and regulate their fates at the post-transcriptional level. One such RBP is ELAVL1. Although significant progress has been made in understanding how embryonic lethal vision-like protein 1 (ELAVL1) regulates mRNAs, its target repertoire and binding distribution within an immunological context remain poorly understood. We overlap four high-throughput approaches to define its context-dependent targets and determine its regulatory impact during immune activation. ELAVL1 transitions from binding overwhelmingly intronic sites to 3' UTR sites upon immune stimulation of cells, binding previously and newly expressed mRNAs. We find that ELAVL1 mediates the RNA stability of genes that regulate pathways essential to pathogen sensing and cytokine production. Our findings reveal the importance of examining RBP regulatory impact under dynamic transcriptomic events to understand their post-transcriptional regulatory roles within specific biological circuitries.

SUBMITTER: Rothamel K

PROVIDER: S-EPMC8225249 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ELAVL1 Primarily Couples mRNA Stability with the 3'UTRs of Interferon Stimulated Genes

Project description:Upon detection of a pathogen, the innate immune system triggers signaling events leading to the transcription of mRNAs that encode for pro-inflammatory and anti-microbial effectors. RNA-binding proteins (RBPs) interact with these functionally critical mRNAs and temporally regulate their fates at the post-transcriptional level. One such RBP is ELAVL1, which is known to bind to introns and 3’UTRs. While significant progress has been made in understanding how ELAVL1 regulates mRNAs, how its target repertoire and binding affinity changes within an immunological context remains poorly understood. Here, we overlap four distinct high-throughput approaches to define its cell-type and context-dependent targets and determine its regulatory impact during immune activation. ELAVL1 overwhelmingly binds to intronic sites in a naïve state, but during an innate immune response, ELAVL1 targets the 3’UTR  binding both previously and newly expressed mRNAs. We find that ELAVL1 mediates the RNA stability of genes that regulate the pathways involved in pathogen sensing and cytokine production. Our findings reveal the importance of examining RBP regulatory impact under dynamic transcriptomic events to best understand their post-transcriptional regulatory roles within specific biological circuitries.

2020-09-01 | GSE157052 | GEO

ELAVL1 Primarily Couples mRNA Stability with the 3'UTRs of Interferon Stimulated Genes

Project description:ELAVL1 Primarily Couples mRNA Stability with the 3'UTRs of Interferon Stimulated Genes

| PRJNA659987 | ENA

Role of the Akt pathway in mRNA translation of interferon-stimulated genes.

Project description:Multiple signaling pathways are engaged by the type I and II IFN receptors, but their specific roles and possible coordination in the generation of IFN-mediated biological responses remain unknown. We provide evidence that activation of Akt kinases is required for IFN-inducible engagement of the mTOR/p70 S6 kinase pathway. Our data establish that Akt activity is essential for up-regulation of key IFN-alpha- and IFN-gamma-inducible proteins, which have important functional consequences in the induction of IFN responses. Such effects of the Akt pathway are unrelated to regulatory activities on IFN-dependent STAT phosphorylation/activation or transcriptional regulation. By contrast, they reflect regulatory activities on mRNA translation via direct control of the mTOR pathway. In studies using Akt1 and Akt2 double knockout cells, we found that the absence of Akt kinases results in dramatic reduction in IFN-induced antiviral responses, establishing a critical role of the Akt pathway in IFN signaling. Thus, activation of the Akt pathway by the IFN receptors complements the function of IFN-activated JAK-STAT pathways, by allowing mRNA translation of IFN-stimulated genes and, ultimately, the induction of the biological effects of IFNs.

| S-EPMC2290753 | biostudies-literature

Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability

Project description:This SuperSeries is composed of the SubSeries listed below.

2011-08-19 | GSE29780 | GEO

Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability [sequence data]

Project description:RNA-binding proteins coordinate the fates of multiple RNAs, but the principles underlying these global interactions remain poorly understood. We elucidated regulatory mechanisms of the RNA-binding protein HuR, by integrating data from diverse high-throughput targeting technologies, specifically PAR-CLIP, RIP-chip, and whole-transcript expression profiling. The number of binding sites per transcript, degree of HuR-association, and degree of HuR-dependent RNA stabilization were positively correlated. Pre-mRNA and mature mRNA containing both intronic and 3' UTR binding sites were more highly stabilized than transcripts with only 3' UTR or only intronic binding sites, suggesting that HuR couples pre-mRNA processing with mature mRNA stability. We also observed HuR-dependent splicing changes and substantial binding of HuR in poly-pyrimidine tracts of pre-mRNAs. Comparison of the spatial patterns surrounding HuR and miRNA binding sites provided functional evidence for HuR-dependent antagonism of proximal miRNA-mediated repression. We conclude that HuR coordinates gene expression outcomes at multiple interconnected steps of RNA processing. HuR (ELAVL1) PAR-CLIP

2011-08-19 | E-GEOD-29779 | biostudies-arrayexpress

Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability [sequence data]

2011-08-19 | GSE29779 | GEO

The mRNA Cap 2'-O-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes.

Project description:Type I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection are unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2'-O-methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2'-O-methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.IMPORTANCE Induction of an efficient type I IFN response is important to control viral infection. We show that the host 2'-O-methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of those mRNAs lacking cap 2'-O-methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

| S-EPMC7227766 | biostudies-literature

Interferon-stimulated genes: roles in viral pathogenesis.

Project description:Interferon-stimulated genes (ISGs) are critical for controlling virus infections. As new antiviral ISGs continue to be identified and characterized, their roles in viral pathogenesis are also being explored in more detail. Our current understanding of how ISGs impact viral pathogenesis comes largely from studies in knockout mice, with isolated examples from human clinical data. This review outlines recent developments on the contributions of various ISGs to viral disease outcomes in vivo.

| S-EPMC4077717 | biostudies-literature

Global Interferon-stimulated Genes Interactome Network

Project description:Interferon-stimulated genes (ISGs) form the backbone of innate immune system and are pivotal for limiting intra- and intercellular viral replication and spread. We conducted a mass spectrometry–based survey to understand the fundamental organization of the innate immune system and to explore molecular functions of individual ISGs. We identified interactions between 104 ISGs and 1,401 cellular binding partners engaging in 2,734 high-confidence interactions. 90% of these interactions are unreported so far, and our survey therefore illuminates a far wider activity spectrum of ISGs than currently known. Integration of the resulting ISG-interaction network with published datasets and functional studies allowed us to identify novel regulators of immunity and immune system–related processes. Given the extraordinary robustness of the innate immune system, this ISG network may serve as a blueprint for therapeutic targeting of cellular systems in order to efficiently fight viral infections.

2019-03-01 | PXD012274 | Pride

Elavl1 Impacts Osteogenic Differentiation and mRNA Levels of Genes Involved in ECM Organization.

Project description:Posttranscriptional gene regulation by Adenylate Uridylate (AU) rich element RNA binding protein, Elavl1 has been implicated in embryonic development as well as progenitor cell differentiation. Elavl1 binds to hundreds of cellular messenger RNAs predominantly through interactions with AU-rich elements (AREs) found in the untranslated regions (UTRs) and functions by regulating their stability. Biological functions of Elavl1 during osteogenic differentiation of bone marrow derived mesenchymal stem cells is not well-understood. Here we report that specific knockdown of nuclear localized Elavl1 by RNA interference in multipotent BMSCs led to increased osteogenic differentiation. Differential gene expression analysis following unbiased total RNA sequencing upon Elavl1 depletion during osteogenic differentiation of BMSCs showed increased levels of multiple mRNAs that are involved in extracellular matrix organization. We further show that many of these mRNAs contain Elavl1 binding consensus motifs that are preserved in their 3' UTRs. RNA stability analyses indicated that depletion of Elavl1 prolongs the steady state RNA levels of several of these mRNAs. Together, our data points to Elavl1 mediated negative regulation of multiple genes involved in ECM organization that play a functional role in MSC osteogenic differentiation.

| S-EPMC7889968 | biostudies-literature

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