RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases
Specific sequences within RNA encoded by human genes essential for survival possess the ability to activate the RNA-dependent stress kinase PKR, resulting in phosphorylation of its substrate, eukaryotic translation initiation factor-2α (eIF2α), either to curb their mRNA translation or to enhance mRN...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/2/1323 |
| _version_ | 1797339759583952896 |
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| author | Raymond Kaempfer |
| author_facet | Raymond Kaempfer |
| author_sort | Raymond Kaempfer |
| collection | DOAJ |
| description | Specific sequences within RNA encoded by human genes essential for survival possess the ability to activate the RNA-dependent stress kinase PKR, resulting in phosphorylation of its substrate, eukaryotic translation initiation factor-2α (eIF2α), either to curb their mRNA translation or to enhance mRNA splicing. Thus, <i>interferon-γ</i> (<i>IFNG</i>) mRNA activates PKR through a 5′-terminal 203-nucleotide pseudoknot structure, thereby strongly downregulating its own translation and preventing a harmful hyper-inflammatory response. <i>Tumor necrosis factor-α</i> (<i>TNF</i>) pre-mRNA encodes within the 3′-untranslated region (3′-UTR) a 104-nucleotide RNA pseudoknot that activates PKR to enhance its splicing by an order of magnitude while leaving mRNA translation intact, thereby promoting effective TNF protein expression. Adult and fetal <i>globin</i> genes encode pre-mRNA structures that strongly activate PKR, leading to eIF2α phosphorylation that greatly enhances spliceosome assembly and splicing, yet also structures that silence PKR activation upon splicing to allow for unabated <i>globin</i> mRNA translation essential for life. Regulatory circuits resulting in each case from PKR activation were reviewed previously. Here, we analyze mutations within these genes created to delineate the RNA structures that activate PKR and to deconvolute their folding. Given the critical role of intragenic RNA activators of PKR in gene regulation, such mutations reveal novel potential RNA targets for human disease. |
| first_indexed | 2024-03-08T09:53:03Z |
| format | Article |
| id | doaj.art-94e8b8b8bc3340e29528927152c48a71 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T09:53:03Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-94e8b8b8bc3340e29528927152c48a712024-01-29T13:59:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-01252132310.3390/ijms25021323RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary DiseasesRaymond Kaempfer0Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 9112102, IsraelSpecific sequences within RNA encoded by human genes essential for survival possess the ability to activate the RNA-dependent stress kinase PKR, resulting in phosphorylation of its substrate, eukaryotic translation initiation factor-2α (eIF2α), either to curb their mRNA translation or to enhance mRNA splicing. Thus, <i>interferon-γ</i> (<i>IFNG</i>) mRNA activates PKR through a 5′-terminal 203-nucleotide pseudoknot structure, thereby strongly downregulating its own translation and preventing a harmful hyper-inflammatory response. <i>Tumor necrosis factor-α</i> (<i>TNF</i>) pre-mRNA encodes within the 3′-untranslated region (3′-UTR) a 104-nucleotide RNA pseudoknot that activates PKR to enhance its splicing by an order of magnitude while leaving mRNA translation intact, thereby promoting effective TNF protein expression. Adult and fetal <i>globin</i> genes encode pre-mRNA structures that strongly activate PKR, leading to eIF2α phosphorylation that greatly enhances spliceosome assembly and splicing, yet also structures that silence PKR activation upon splicing to allow for unabated <i>globin</i> mRNA translation essential for life. Regulatory circuits resulting in each case from PKR activation were reviewed previously. Here, we analyze mutations within these genes created to delineate the RNA structures that activate PKR and to deconvolute their folding. Given the critical role of intragenic RNA activators of PKR in gene regulation, such mutations reveal novel potential RNA targets for human disease.https://www.mdpi.com/1422-0067/25/2/1323PKR activationRNA splicingtranslationinflammatory cytokine genes<i>IFNG</i> RNA<i>TNF</i> RNA |
| spellingShingle | Raymond Kaempfer RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases International Journal of Molecular Sciences PKR activation RNA splicing translation inflammatory cytokine genes <i>IFNG</i> RNA <i>TNF</i> RNA |
| title | RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases |
| title_full | RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases |
| title_fullStr | RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases |
| title_full_unstemmed | RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases |
| title_short | RNA Activators of Stress Kinase PKR within Human Genes That Control Splicing or Translation Create Novel Targets for Hereditary Diseases |
| title_sort | rna activators of stress kinase pkr within human genes that control splicing or translation create novel targets for hereditary diseases |
| topic | PKR activation RNA splicing translation inflammatory cytokine genes <i>IFNG</i> RNA <i>TNF</i> RNA |
| url | https://www.mdpi.com/1422-0067/25/2/1323 |
| work_keys_str_mv | AT raymondkaempfer rnaactivatorsofstresskinasepkrwithinhumangenesthatcontrolsplicingortranslationcreatenoveltargetsforhereditarydiseases |