First panel: NOD proteins reside in an inactive state in the cytoplasm, where they serve as sensors for various bacterial components. Second panel: degradation of bacterial cell-wall peptidoglycans produces muramyl dipeptide, which is recognized by NOD2. NOD1 recognizes γ-glutamyl diaminopimelic acid (iE-DAP), a breakdown product of Gram-negative bacterial cell walls. The binding of these ligands to NOD1 or NOD2 induces aggregation, allowing CARD-dependent recruitment of the serine– threonine kinase RIP2, which associates with E3 ligases, including XIAP (X-linked inhibitor of apoptosis protein), cIAP1 (cellular inhibitor of apoptosis 1), and cIAP2. This recruited E3 ligase activity produces a polyubiquitin scaffold, as in TLR signaling, and the association of TAK1 and the IKK complex with this scaffold leads to the activation of NFκB, as shown in Fig. 3.15. In this pathway, RIP2 acts as a scaffold to recruit XIAP, and RIP2 kinase activity is not required for signaling.
Fig. 3.18 Protein-interaction domains contained in various immune signaling molecules. Signaling proteins contain protein-interaction domains that mediate the assembly of larger complexes. The table shows examples of proteins discussed in this chapter that contain the indicated domain. Proteins may have more than one domain, such as the adaptor protein MyD88, which can interact with TLRs via its TIR domain and with IRAK1/4 via its death domain (DD).
MOVIE 3.6
Fig. 3.19 Cellular damage activates the NLRP3 inflammasome to produce pro-inflammatory cytokines.
The LRR domain of NLRP3 associates with chaperones (HSP90 and SGT1) that prevent NLRP3 activation. Damage to cells caused by bacterial pore-forming toxins or activation of the P2X7 receptor by extracellular ATP allows efflux of K+ ions from the cell; this may dissociate these chaperones from NLRP3 and induce multiple NLRP3 molecules to aggregate through interactions of their NOD domains (also called the NACHT domain). Reactive oxygen intermediates (ROS) and disruption of lysosomes also can activate NLRP3 (see text). The aggregated NLRP3 conformation brings multiple NLRP3 pyrin domains into close proximity, which then interact with the pyrin domains of the adaptor protein ASC (PYCARD). This conformation aggregates the ASC CARD domains, which in turn aggregate the CARD domains of pro-caspase 1. This aggregation of procaspase 1 induces proteolytic cleavage of itself to form the active caspase 1, which cleaves the immature forms of pro-inflammatory cytokines, releasing the mature cytokines that are then secreted.
increase basal activation of neutrophils. A reduction in neutrophils activated in this way may explain why mice lacking NOD1 show increased susceptibility even to pathogens that lack NOD ligands, such as the parasite Trypanosoma cruzi.