Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response
Abstract The cellular recognition of viruses evokes the secretion of type‐I interferons (IFNs) that induce an antiviral protective state. By live‐cell imaging, we show that key steps of virus‐induced signal transduction, IFN‐β expression, and induction of IFN‐stimulated genes (ISGs) are stochastic e...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2012-05-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/msb.2012.17 |
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| _version_ | 1849389421373161472 |
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| author | Ulfert Rand Melanie Rinas Johannes Schwerk Gesa Nöhren Melanie Linnes Andrea Kröger Michael Flossdorf Kristóf Kály‐Kullai Hansjörg Hauser Thomas Höfer Mario Köster |
| author_facet | Ulfert Rand Melanie Rinas Johannes Schwerk Gesa Nöhren Melanie Linnes Andrea Kröger Michael Flossdorf Kristóf Kály‐Kullai Hansjörg Hauser Thomas Höfer Mario Köster |
| author_sort | Ulfert Rand |
| collection | DOAJ |
| description | Abstract The cellular recognition of viruses evokes the secretion of type‐I interferons (IFNs) that induce an antiviral protective state. By live‐cell imaging, we show that key steps of virus‐induced signal transduction, IFN‐β expression, and induction of IFN‐stimulated genes (ISGs) are stochastic events in individual cells. The heterogeneity in IFN production is of cellular—and not viral—origin, and temporal unpredictability of IFN‐β expression is largely due to cell‐intrinsic noise generated both upstream and downstream of the activation of nuclear factor‐κB and IFN regulatory factor transcription factors. Subsequent ISG induction occurs as a stochastic all‐or‐nothing switch, where the responding cells are protected against virus replication. Mathematical modelling and experimental validation show that reliable antiviral protection in the face of multi‐layered cellular stochasticity is achieved by paracrine response amplification. Achieving coherent responses through intercellular communication is likely to be a more widely used strategy by mammalian cells to cope with pervasive stochasticity in signalling and gene expression. |
| format | Article |
| id | doaj-art-7f837d2b0b1f40dcac2982f38342f341 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2012-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-7f837d2b0b1f40dcac2982f38342f3412025-08-20T03:41:57ZengSpringer NatureMolecular Systems Biology1744-42922012-05-018111310.1038/msb.2012.17Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon responseUlfert Rand0Melanie Rinas1Johannes Schwerk2Gesa Nöhren3Melanie Linnes4Andrea Kröger5Michael Flossdorf6Kristóf Kály‐Kullai7Hansjörg Hauser8Thomas Höfer9Mario Köster10Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchDivision of Theoretical Systems Biology, German Cancer Research Center (DKFZ) and BioQuant CenterDepartment of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchDepartment of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchDepartment of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchDepartment of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchDivision of Theoretical Systems Biology, German Cancer Research Center (DKFZ) and BioQuant CenterDivision of Theoretical Systems Biology, German Cancer Research Center (DKFZ) and BioQuant CenterDepartment of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchDivision of Theoretical Systems Biology, German Cancer Research Center (DKFZ) and BioQuant CenterDepartment of Gene Regulation and Differentiation, Helmholtz Centre for Infection ResearchAbstract The cellular recognition of viruses evokes the secretion of type‐I interferons (IFNs) that induce an antiviral protective state. By live‐cell imaging, we show that key steps of virus‐induced signal transduction, IFN‐β expression, and induction of IFN‐stimulated genes (ISGs) are stochastic events in individual cells. The heterogeneity in IFN production is of cellular—and not viral—origin, and temporal unpredictability of IFN‐β expression is largely due to cell‐intrinsic noise generated both upstream and downstream of the activation of nuclear factor‐κB and IFN regulatory factor transcription factors. Subsequent ISG induction occurs as a stochastic all‐or‐nothing switch, where the responding cells are protected against virus replication. Mathematical modelling and experimental validation show that reliable antiviral protection in the face of multi‐layered cellular stochasticity is achieved by paracrine response amplification. Achieving coherent responses through intercellular communication is likely to be a more widely used strategy by mammalian cells to cope with pervasive stochasticity in signalling and gene expression.https://doi.org/10.1038/msb.2012.17bacterial artificial chromosomesgene expressioninterferon regulatory factor‐7live‐cell microscopymulti‐scale modelling |
| spellingShingle | Ulfert Rand Melanie Rinas Johannes Schwerk Gesa Nöhren Melanie Linnes Andrea Kröger Michael Flossdorf Kristóf Kály‐Kullai Hansjörg Hauser Thomas Höfer Mario Köster Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response Molecular Systems Biology bacterial artificial chromosomes gene expression interferon regulatory factor‐7 live‐cell microscopy multi‐scale modelling |
| title | Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response |
| title_full | Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response |
| title_fullStr | Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response |
| title_full_unstemmed | Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response |
| title_short | Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response |
| title_sort | multi layered stochasticity and paracrine signal propagation shape the type i interferon response |
| topic | bacterial artificial chromosomes gene expression interferon regulatory factor‐7 live‐cell microscopy multi‐scale modelling |
| url | https://doi.org/10.1038/msb.2012.17 |
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