Box 1. Primer on TNF signaling to NF-B

Upon binding of TNF (1), TNF receptor (TNFR) is activated, leading to activation of the IB kinase (IKK) (2). IKK dually phosphorylates inhibitor of NF-B (IB) (3), which in a basal state holds NF-B latent in the cytoplasm. Phosphorylated IB is targeted for ubiquitination (4) and subsequently proteosome-mediated degradation (5). NF-B, no longer bound to IB, enters the nucleus (6) where it may modulate gene transcription. The genes for IB are among the genes that are upregulated by NF-B (7). Newly synthesized IBenters the nucleus, binds to NF-B, and promotes its export to the cytoplasm (8), thereby forming a negative feedback loop that terminates the response. New IB–NF-B complexes may enter the feedback loop, beginning with phosphorylation by IKK, if TNF stimulation persists (9). There are three typical isoforms of IB: IB, IB, and IB. As discussed in the main text, expression of IB is robustly induced by NF-B and was a focus of initial modeling studies of the pathway, whereas NF-B-induced expression of IB and IB was a topic of later investigations.