How the noninflammasome NLRs function in the innate immune system

Abstract

NLR (nucleotide-binding domain, leucine-rich repeat-containing) proteins have rapidly emerged as central regulators of immunity and inflammation with demonstrated relevance to human diseases. Much attention has focused on the ability of several NLRs to activate the inflammasome complex and drive proteolytic processing of inflammatory cytokines; however, NLRs also regulate important inflammasome-independent functions in the immune system. We discuss several of these functions, including the regulation of canonical and noncanonical NF-kappaB activation, mitogen-activated protein kinase activation, cytokine and chemokine production, antimicrobial reactive oxygen species production, type I interferon production, and ribonuclease L activity. We also explore the mechanistic basis of these functions and describe current challenges in the field.

Fig. 1

NOD2 signaling bifurcates into antibacterial and antiviral effector arms. A model of NOD2 signaling is presented in which NOD2 is bound to the chaperonin and ubiquitin ligase pair, HSP90 and SGT in the basal state (Complex A). This is thought to hold the inactive NOD2 in a signaling competent form (48). Upon stimulation with MDP, NOD2 binds to RIP2, and activates NF-κB and MAPK (p38 and JNK) through recruitment of several intracellular proteins, including cIAP1 and cIAP2 (Complex B). This leads to in the induction of chemokines, cytokines and defensins, which mediate the antimicrobial responses. Similarly, viral infection can activate NOD2, leading to its translocation to the mitochondria, association with MAVS, and the induction of the antiviral cytokine, type I interferon (Complex C). Double stranded RNA, and possibly single stranded RNA, induces OAS-2 to interact with NOD2. NOD2 then stimulates the production of -5’ oligoadenylate synthase type 2, which activates antiviral responses including RNaseL activation (Complex C). RIG-I is depicted because it is the PRR that binds to viral nucleic acids, while TBK and IKK-e lies downstream of MAVS to activate IRF-3.

Fig. 2

NLR proteins and regulation of the mito-signalosome. In the quiescent state (Complex A), the CARD:CARD homotypic interaction between MAVS and RIG-I is prevented by MAVS association with NLRX1, Atg5-Atg12 conjugate, perhaps by steric hindrance. Mfn2 interacts with the C-terminus and the transmembrane region of MAVS to abolish its immune-activating function. The three regulatory proteins target different regions of MAVS to execute the “molecular brake”. In the presence of cytosolic 5'-triphosphate single stranded RNA or double stranded RNA, these brakes are released, which renders the assembly of the active form of mitosignalosome (Complex B), in which MAVS interacts with NOD2 and RLRs, such as RIG-I, which directly interact with viral nucleic acid to trigger type I IFN production.

Fig. 3

NLR proteins signal through different multi-component signalosomes. NLR signaling modules include the CIITA transcriptosome, the caspase-1 activating inflammasomes, the interferon/cytokine inducing mito-signalosome, the NF-kB/MAPK activating NOD1/2 complex (referred to as the NODosome), and the NIK pathway. This figure depicts the concept that one NLR can serve multiple functions, while multiple NLRs can also serve similar functions.