NF-κB signaling dynamics is controlled by a dose-sensing autoregulatory loop
| Autor: | Markus W. Covert, Miriam V. Gutschow, Helen R. Clark, Mialy M. DeFelice, Jacob J. Hughey, Inbal Maayan, Takamasa Kudo, Sergi Regot |
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| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Interleukin-1beta Stimulus (physiology) Optogenetics Biology Biochemistry Time-Lapse Imaging Article 03 medical and health sciences Mice 0302 clinical medicine Animals Humans Kinase activity Receptor Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences Innate immune system Microscopy Confocal Dose-Response Relationship Drug Tumor Necrosis Factor-alpha HEK 293 cells Toll-Like Receptors NF-kappa B NF-kappa B p50 Subunit IRAK1 Cell Biology Cell biology HEK293 Cells Interleukin-1 Receptor-Associated Kinases Myeloid Differentiation Factor 88 NIH 3T3 Cells Single-Cell Analysis 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Science signaling. 12(579) |
| ISSN: | 1937-9145 |
| Popis: | Over the last decade, multiple studies have shown that signaling proteins activated in different temporal patterns—such as oscillatory, transient, and sustained—can result in distinct gene expression patterns or cell fates. However, the molecular events that ensure appropriate stimulus- and dose-dependent dynamics are not often understood and are difficult to investigate. Here, we used single-cell analysis to dissect the mechanisms underlying the stimulus- and dose-encoding patterns in the innate immune signaling network. We found that Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling dynamics relied on a dose-dependent, auto-inhibitory loop that rendered cells refractory to further stimulation. Using inducible gene expression and optogenetics to perturb the network at different levels, we identified the IL-1R–associated kinase1 (IRAK1) as the dose-sensing node responsible for limiting signal flow during the innate immune response. Although the kinase activity of IRAK1 was not required for signal propagation, it played a critical role in inhibiting the nucleocytoplasmic oscillations of the transcription factor NF-κB. Thus, protein activities that may be “dispensable” from a topological perspective can nevertheless be essential in shaping the dynamic response to the external environment. |
| Databáze: | OpenAIRE |
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