NOD-like receptor (NLR) signaling beyond the inflammasome

Abstract

Recent years have witnessed a marked progress in our knowledge of NOD-like receptors (NLR), intracellular sensors with central roles in innate and adaptive immunity. A majority of the research has focused on caspase-1 inflammasomes. However, several members of the mammalian NLR family exert important roles in immunity beyond inflammasome signaling. Here we highlight the emerging roles of several of these NLR.

Figure 1. The structure and primary functions of some of the NLR proteins

Figure 2. Summary of NLR functions beyond the inflammasome

NOD1 and NOD2 recognize peptidoglycan fragments released either during bacterial division within the cytosol or by the lysosome during the degradation of phagocytosed bacteria. Activation of either NOD1 or NOD2 leads to the recruitment and activation of RIP2, which results in MAPK pathway and NF-κB activation. NLRP12 acts to silence MAPK and NF-κB activation. These pathways are also activated by the recognition of bacterial components by TLRs. NLRP12 inhibits the phosphorylation of interleukin-1 receptor-associated kinase 1 (IRAK-1), therefore blocking MAPK and NF-κB activation. CIITA is a transcriptional factor induced by IFNγ signaling pathways. CIITA binds to the enhanceosome and is the master regulator of MHC II expression. NLRX1 function and localization is controversial and there are two potential mechanisms of action, which are not mutually exclusive. The first proposes that NLRX1 is imported into the mitochondrial matrix by TOM/TIM. Once in the matrix, the mitochondrial leader sequence is cleaved from the N-terminal sequence and NLRX1 interacts with the core II protein (UQRC2) of complex III of the mitochondrial respiratory chain. This interaction results in the production of ROS, which activate JNK and NF-kB signaling pathways. The second proposes that NLRX1 is localized to the mitochondrial outer membrane, where it interacts with MAVS. This interaction prevents MAVS from interacting with RIG-I when it senses viral RNA. The resulting effect is the inhibition of immune responses induced by viral RNA recognition.