Non-Inflammasome Forming NLRs in Inflammation and Tumorigenesis

Abstract

Aberrant inflammation is an enabling characteristic of tumorigenesis. Thus, signaling cascades that alter inflammatory activation and resolution are of specific relevance to disease pathogenesis. Pattern recognition receptors (PRRs) are essential mediators of the host immune response and have emerged as critical elements affecting multiple facets of tumor pathobiology. The nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins are intracellular PRRs that sense microbial and non-microbial products. Members of the NLR family can be divided into functional sub-groups based on their ability to either positively or negatively regulate the host immune response. Recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively regulate diverse biological pathways associated with both inflammation and tumorigenesis. Understanding the mechanisms underlying the function of these unique NLRs will assist in the rationale design of future therapeutic strategies targeting a wide spectrum of inflammatory diseases and cancer. Here, we will discuss recent findings associated with this novel NLR sub-group and mechanisms by which these PRRs may function to alter cancer pathogenesis.

Keywords: NF-κB; NLRC3; NLRP12; NLRX1; Nod-like receptors; TRAF; cancer; pattern recognition receptors.

Figure 1

Schematic illustrating NLR attenuation of canonical and non-canonical NF-κB signaling. NF-κB is a master regulator of gene transcription and contributes to several hallmarks of cancer. NLRX1, NLRP12, and NLRC3 negatively regulate NF-κB signaling at multiple levels. NLRX1 interacts with and inhibits TRAF6 and the IKK complex resulting in the attenuation of NF-κB signaling following TLR stimulation. Likewise, NLRC3 was also shown to interact with TRAF6 and attenuate NF-κB signaling through a similar mechanism. NLRP12, has been shown to attenuate both the canonical NF-κB signaling pathway through modulating the phosphorylation of IRAK-1 and the non-canonical NF-κB pathway through interactions with TRAF3 and NIK.

Figure 2

Schematic illustrating NLRX1 regulation of type-I interferon, ROS and autophagy signaling. NLRX1 is localized to the mitochondria, where it has been shown to bind with MAVS and prevent the interaction between MAVS and RIG-I during the host anti-viral response. This interaction significantly attenuates MAVS activation of IRF3 and IRF7 and results in reduced IFN and IL-6 signaling. NLRX1 has also been shown to function as a positive regulator of autophagy through its interactions with the mitochondrial protein TUFM, and the mitochondrial immune signaling complex (MISC), which includes Atg5–Atg12 and ATG16L1. This complex has been shown to be important in promoting virus-induced autophagy and concurrently attenuating IFN signaling. In addition to its role in attenuating host anti-viral signaling, NLRX1 has also been shown to significantly augment ROS generation from the mitochondria through interactions with UQCRC2 following infection with specific species of bacteria.