Stochastic pooling of IKK/NEMO complexes describes information transmission in the NF-KB pathway in response to IL-1 and TNF stimulation

• Published in: The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.106-106.07
• Main Authors: Cruz, J. Agustin, Mokashi, Chaitanya, Lee, Robin E.C.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.106.07

A myriad of inflammatory cytokines regulates signaling pathways for normal cellular physiology. The IKK complex is an integration hub for extracellular cytokines that govern NF-κB signaling. In response to inflammation, IKK is activated through recruitment to receptor-associated protein assemblies. How and what information IKK complexes transmit about the milieu are open questions. Here we track dynamics of IKK complexes and nuclear NF-κB to identify upstream signaling features that determine same-cell responses. Quantitative imaging experiments and computational modeling of single complexes reveals that their size, number, and timing relays cytokine-specific information with feedback control that is independent of transcription. Our results provide evidence for variable-gain stochastic pooling, a noise-reducing motif that enables parsimonious and cytokine-specific signaling. We argue that emergent properties of stochastic pooling motif are general principles of receptor signaling, and we present new modules of regulation of NF-kB signaling in response to cytokine stimulation.