Maiwald, Tim and Schneider, Annette and Busch, Hauke and Sahle, Sven and Gretz, Norbert and Weiss, Thomas S. and Kummer, Ursula and Klingmueller, Ursula (2010) Combining theoretical analysis and experimental data generation reveals IRF9 as a crucial factor for accelerating interferon alpha-induced early antiviral signalling. FEBS JOURNAL, 277 (22). pp. 4741-4754. ISSN 1742-464X, 1742-4658
Full text not available from this repository. (Request a copy)Abstract
Type I interferons (IFN) are important components of the innate antiviral response. A key signalling pathway activated by IFN alpha is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Major components of the pathway have been identified. However, critical kinetic properties that facilitate accelerated initiation of intracellular antiviral signalling and thereby promote virus elimination remain to be determined. By combining mathematical modelling with experimental analysis, we show that control of dynamic behaviour is not distributed among several pathway components but can be primarily attributed to interferon regulatory factor 9 (IRF9), constituting a positive feedback loop. Model simulations revealed that increasing the initial IRF9 concentration reduced the time to peak, increased the amplitude and enhanced termination of pathway activation. These model predictions were experimentally verified by IRF9 over-expression studies. Furthermore, acceleration of signal processing was linked to more rapid and enhanced expression of IFN alpha target genes. Thus, the amount of cellular IRF9 is a crucial determinant for amplification of early dynamics of IFN alpha-mediated signal transduction.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSCRIPTION FACTOR ISGF3; DEPENDENT PROTEIN-KINASE; CHRONIC HEPATITIS-C; BIOLOGICAL NETWORKS; QUANTITATIVE DATA; GAMMA-INTERFERON; SYSTEMS BIOLOGY; GENE INDUCTION; IFN-ALPHA; STAT; antiviral signalling; interferon alpha; IRF9; kinetic model; signal transduction |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Jul 2020 07:06 |
| Last Modified: | 07 Jul 2020 07:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/23936 |
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