Various cell-surface receptors activate the NFκB signaling pathway in animal cells. Toll receptors in Drosophila and Toll-like receptors in vertebrates, for example, recognize pathogens and activate this pathway in triggering innate immune responses (discussed in Chapter 24). The receptors for tumor necrosis factor α (TNFα) and interleukin-1 (IL1), which are vertebrate cytokines especially important in inducing inflammatory responses, also activate this signaling pathway. The Toll, Toll-like, and IL1 receptors belong to the same family of proteins, whereas TNF receptors belong to a different family; all of them, however, act in similar ways to activate NFκB. When activated, they trigger a multiprotein ubiquitylation and phosphorylation cascade that releases NFκB from an inhibitory protein complex, so that it can translocate to the nucleus and turn on the transcription of hundreds of genes that participate in inflammatory and innate immune responses.
There are five NFκB proteins in mammals (RelA, RelB, c-Rel, NFκB1, and NFκB2), and they form a variety of homodimers and heterodimers, each of which activates its own characteristic set of genes. Inhibitory proteins called IκB bind tightly to the dimers and hold them in an inactive state within the cytoplasm of unstimulated cells. There are three major IκB proteins in mammals (IκB α, β, and ε), and the signals that release NFκB dimers do so by triggering a signaling pathway that leads to the phosphorylation, ubiquitylation, and consequent degradation of the IκB proteins (Figure 15–62).
Among the genes activated by the released NFκB is the gene that encodes IκBα. This activation leads to increased synthesis of IκBα protein, which binds to NFκB and inactivates it, creating a negative feedback loop (Figure 15–63A). Experiments on TNFα-induced responses, as well as computer modeling studies of the responses, indicate that the negative feedback produces two types of NFκB responses, depending on the duration of the TNFα stimulus; importantly, the two types of responses induce different patterns of gene expression (Figure 15–63B, C, and D). The negative feedback through IκBα is required for both types of responses: in cells deficient in IκBα, even a short exposure to TNFαinduces a sustained activation of NFκB, without oscillations, and all of the NFκB-responsive genes are activated.
Thus far, we have focused on the mechanisms by which extracellular signal molecules use cell-surface receptors to initiate changes in gene expression. We now turn to a class of extracellular signals that bypasses the plasma membrane entirely and controls, in the most direct way possible, transcription regulatory proteins inside the cell.
Various small, hydrophobic signal molecules diffuse directly across the plasma membrane of target cells and bind to intracellular receptors that are transcription regulators. These signal molecules include steroid hormones, thyroid hormones, retinoids, and vitamin D. Although they differ greatly from one another in both