NOD-like receptors (NLRs): bona fide intracellular microbial sensors

Abstract

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) (nucleotide-binding domain leucine-rich repeat containing) family of proteins has been demonstrated to function as regulators of innate immune response against microbial pathogens. Stimulation of NOD1 and NOD2, two prototypic NLRs, results in the activation of MAPK and NF-kappaB. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of an inflammasome. This review discusses recent findings regarding the signaling pathways utilized by NLR proteins in the control of caspase-1 and NF-kappaB activation, as well as the nonredundant role of NLRs in pathogen clearance. The review also covers advances regarding the cellular localization of these proteins and the implications this may have on pathogen sensing and signal transduction.

Figure 1. NOD1/NOD2 activation and signaling

NOD1 and NOD2 sense peptidoglycan-derived motifs in the cytosol and form a complex with RICK. K63-linked regulatory ubiquitination of RICK leads to the recruitment of TAK1. The activation and recruitment of TAK1 complex to RICK further recruits the IKK complex. The interaction between RICK and NEMO ultimately results in the activation of IKKs and MKK by TAK1.

Figure 2. Cellular localization of NOD1 and NOD2

A) During S. flexneri infection NOD1 is recruited to the bacterial entry site. It is unclear whether NOD1 is recruited to the bacterial contact foci from the cytosol or the plasma membrane fraction. Nevertheless, the co-localization of NOD1 with the bacterial contact point suggests that PGN sensing and signaling by NOD1 occurs at this initial site of contact. B) MDP is internalized into an acidified endosomal compartment. NOD2 could be sensing MDP at the plasma membrane and becomes associated with the vesicle following invagination of the plasma membrane during vesicle formation (1). Alternatively, NOD2 could be actively recruited to the MDP-containing vesicle after internalization (2). The localization of MDP to vesicle suggests that NOD2 signaling may be emanating from these vesicular structures. C) NLRX1, a mitochondria-targeted NLR protein, might act as a negative regulator of MAVS signalling, diminishing virally induced RIG-like helicase interactions. In a different model, NLRX1 promotes ROS production at the mitochondria, which consequently helps to fight bacteria and viruses. How NLRX1 is activated remains unclear.

Figure 3. Productive IL-1β secretion is a two-step process

TLR signaling induces the synthesis of pro-IL-1β. Bacteria and/or bacterial products enter the cytosol either through the actions of pore-forming toxins or ATP-mediated activation of the pannexin-1 pore. Activation of NLRs by cytosolic PAMPs promotes the formation of caspase-1 activating ‘inflammasome’. Active caspase-1 then processes the IL-1β precursor into the bioactive form for secretion.