phosphorylates and activates IKKβ. IKKβ then phosphorylates IκB (inhibitor of κB), which is a distinct molecule whose name should not be confused with IKKβ. IκB is a cytoplasmic protein that constitutively binds to the transcription factor NFκB, which is composed of two subunits, p50 and p65. The binding of IκB traps the NFκB proteins in the cytoplasm. Phosphorylation by IKK induces the degradation of IκB, and this releases NFκB into the nucleus, where it can drive transcription of genes for pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. The actions of these cytokines in the innate immune response are described in the second half of this chapter. The outcome of TLR activation can also vary depending on the cell type in which it occurs. For example, activation of TLR-4 via MyD88 in specialized epithelial cells such as the Paneth cells of the intestine (see Section 2-4) results in the production of antimicrobial peptides, a mammalian example of the ancient function of Toll-like proteins.
The ability of TLRs to activate NFκB is crucial to their role of alerting the immune system to the presence of bacterial pathogens. Rare instances of inactivating mutations in IRAK4 in humans cause an immunodeficiency, IRAK4 deficiency, which, like MyD88 deficiency, is characterized by recurrent bacterial infections. Mutations in human NEMO produce a syndrome known as X-linked hypohidrotic ectodermal dysplasia and immunodeficiency or NEMO deficiency, which is characterized by both immunodeficiency and developmental defects.
The nucleic-acid-sensing TLRs—TLR-3, TLR-7, TLR-8, and TLR-9—activate members of the IRF family. IRF proteins reside in the cytoplasm and are inactive until they become phosphorylated on serine and threonine residues in
Left panel: TLR-3, expressed by dendritic cells and macrophages, senses double-stranded viral RNA (dsRNA). TLR-3 signaling uses the adaptor protein TRIF, which recruits the E3 ligase TRAF3 to generate K63-linked polyubiquitin chains. This scaffold recruits NEMO and TANK (TRAF family member-associated NFκB activator), which associate with the serine– threonine kinases IKKε (IκB kinase ε) and TBK1 (TANK-binding kinase 1). TBK1 phosphorylates (red dot) the transcription factor IRF3, and IRF3 then enters the nucleus and induces expression of type I interferon genes. Right panel: TLR-7, expressed by plasmacytoid dendritic cells, detects single-stranded RNA (ssRNA) and signals through MyD88. Here, IRAK1 directly recruits and phosphorylates IRF7, which is also highly expressed in plasmacytoid dendritic cells. IRF7 then enters the nucleus to induce expression of type I interferons.