NF-κB signaling dynamics is controlled by a dose-sensing autoregulatory loop

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-d...

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Bibliographic Details
Published in:Science signaling 2019-04, Vol.12 (579)
Main Authors: DeFelice, Mialy M, Clark, Helen R, Hughey, Jacob J, Maayan, Inbal, Kudo, Takamasa, Gutschow, Miriam V, Covert, Markus W, Regot, Sergi
Format: Article
Language:English
Subjects:
Arthritis
Autoimmune diseases
Biosensors
Control theory
Cytokine receptors
Cytokines
Dynamic response
Feedback loops
Gene expression
Genetics
Hazards
Immune response
Immune system
Infections
Information processing
Innate immunity
Interleukin 1
Interleukin 1 receptors
IRAK protein
Kinases
Mutation
NF-κB protein
Optics
Oscillations
Proteins
Receptors
Rheumatoid arthritis
Signaling
Stimulation
Toll-like receptors
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Summary: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, autoinhibitory loop that rendered cells refractory to further stimulation. Using inducible gene expression and optogenetics to perturb the network at different levels, we identified IL-1R-associated kinase 1 (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.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.aau3568