Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome
Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanism...
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| Format: | Article |
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eLife Sciences Publications Ltd
2025-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/100197 |
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| author | Kira A Cozzolino Lynn Sanford Samuel Hunter Kayla Molison Benjamin Erickson Meaghan CS Courvan Taylor Jones Deepa Ajit Matthew D Galbraith Joaquín M Espinosa David Bentley Mary Ann Allen Robin D Dowell Dylan J Taatjes |
| author_facet | Kira A Cozzolino Lynn Sanford Samuel Hunter Kayla Molison Benjamin Erickson Meaghan CS Courvan Taylor Jones Deepa Ajit Matthew D Galbraith Joaquín M Espinosa David Bentley Mary Ann Allen Robin D Dowell Dylan J Taatjes |
| author_sort | Kira A Cozzolino |
| collection | DOAJ |
| description | Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions. |
| format | Article |
| id | doaj-art-087ed016dfe945e1a852fc55ca07cecb |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-087ed016dfe945e1a852fc55ca07cecb2025-02-11T14:22:57ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.100197Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndromeKira A Cozzolino0Lynn Sanford1Samuel Hunter2Kayla Molison3Benjamin Erickson4Meaghan CS Courvan5Taylor Jones6Deepa Ajit7Matthew D Galbraith8https://orcid.org/0000-0003-0485-3927Joaquín M Espinosa9https://orcid.org/0000-0001-9048-1941David Bentley10Mary Ann Allen11Robin D Dowell12https://orcid.org/0000-0001-7665-9985Dylan J Taatjes13https://orcid.org/0000-0003-4444-5688Department of Biochemistry, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, United States; BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, United States; BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United StatesDepartment of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States; UC-Denver RNA Bioscience Initiative, Aurora, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United States; Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, United States; BioFrontiers Institute, University of Colorado, Boulder, United States; Crnic Institute Boulder Branch, Boulder, United States; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United StatesMetabolon Inc, Durham, Morrisville, United StatesLinda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, United States; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, United StatesLinda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, United States; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, United StatesDepartment of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States; UC-Denver RNA Bioscience Initiative, Aurora, United StatesBioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, United States; BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United StatesHyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.https://elifesciences.org/articles/100197mitochondriacytokineinterferonsDown syndromegene expressionmetabolism |
| spellingShingle | Kira A Cozzolino Lynn Sanford Samuel Hunter Kayla Molison Benjamin Erickson Meaghan CS Courvan Taylor Jones Deepa Ajit Matthew D Galbraith Joaquín M Espinosa David Bentley Mary Ann Allen Robin D Dowell Dylan J Taatjes Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome eLife mitochondria cytokine interferons Down syndrome gene expression metabolism |
| title | Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome |
| title_full | Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome |
| title_fullStr | Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome |
| title_full_unstemmed | Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome |
| title_short | Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome |
| title_sort | mediator kinase inhibition suppresses hyperactive interferon signaling in down syndrome |
| topic | mitochondria cytokine interferons Down syndrome gene expression metabolism |
| url | https://elifesciences.org/articles/100197 |
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