Teleost NOD-like receptors and their downstream signaling pathways: A brief review

Abstract

Nucleotide-binding oligomerization domain-like receptors (NOD-like receptors or NLRs) are key members of the immune system that act as intracellular sentinels. These pathogen recognition receptors are essentially characterized by a central nucleotide binding domain and a C-terminal leucine rich repeat domain responsible for recognition of pathogens. Over the past decade, our understanding of teleosts' NLRs has enhanced significantly although the signaling pathways remain to be elucidated. In this brief review, we have tried to decipher the structural and functional aspects of NLRs in teleost. The review also engages in illustrating the various downstream signaling pathways/molecules reported so far in fishes that enable the NLRs to act as important players in immune responses and defense mechanisms against pathogens. Importantly, we try to explore the lacunae in structural and mechanistic details of NLRs in the teleost that would help in identifying key areas in which research is needed to complete our understanding of NLRs and their structural and functional evolution.

Keywords: NLR; signaling; structural domain; teleosts.

Figure 1

Schematic representation of NOD-like receptors and their signaling pathways in mammals and teleost. MAMPs, PAMPs and DAMPs are recognized by various NLRs. This leads to the activation of downstream signaling cascades resulting in inflammatory responses. (PAMPs- pathogen-associated molecular patterns, DAMPs- damage-associated molecular patterns, MAMPs-microbial-associated molecular patterns, dsRNA-double stranded RNA, LRR- leucine rich repeats, CARD-caspase activation and recruitment domains, NACHT-NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), FISNA- fish-specific NACHT associated, STING- stimulator of interferon genes, NFkB- nuclear factor kappa-light-chain-enhancer of activated B cells, P13K- phosphatidylinositol-3-kinase, AKT- Protein kinase B, mTOR- mammalian target of rapamycin, TLR- Toll-like receptor, IFN- interferon, MDA5- melanoma differentiation-associated protein 5, RIG-1- retinoid acid -inducible gene I, JNK- janus kinase, STAT- signal transducers and activators of transcription, VEGF- Vascular endothelial growth factor, MHC- major histocompatibility complex).

Figure 2

Domain architecture of NLRs in teleosts. NLRs are broadly divided into three subfamilies namely NLR-A, NLR-B and NLR-C. Members of NLR-A subfamily have a varied number of CARD domains at the N-terminal. NLR-B family has been characterized in three fish species (zebrafish, channel catfish, miiuy croaker) so far. ‘#’ denotes domain organization depending on fish species. NLR-B1 in zebrafish contains CARD, NACHT and LRR domains whereas in channel catfish and miiuy croaker, the LRR domain is reported to be absent. ‘*’ denotes that differential domain organization in NLR-B2 wherein both CARD and NACHT domains are present in zebrafish while only NACHT domain in channel catfish and CARD domain in miiuy croaker. NLR-C subfamily is unique to teleosts with different domain organization across species and within the same species. Till date, the N-terminal domain of NLRX1 remains unidentified. (LRR- leucine rich repeats, BIR- baculovirus IAP repeat, CARD-caspase activation and recruitment domains, NACHT-NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein), FISNA- fish-specific NACHT associated).

Figure 3

Nodosome signaling pathways. NOD1 and NOD2 after sensing PAMPs interact with RIPK leading to induction of pro-inflammatory cytokines via NF-kB pathway. In mammals, NOD2 is also reported to interact with TAK1 and GRIM-19 to induce NF-kB pathway. NOD1 and NOD2 are involved in synthesis of anti-microbial peptides via ERK and NOD1 interacts with COP9 signalosome to bring about apoptosis. RIPK also interacts with ASC and activate caspase-1 involved in processing of pro-inflammatory cytokines. In addition, NOD2 is also seen to interact with MAVS either via RIG-1, MDA5 or directly in response to ssRNA virus and might induce IFN gene expression in case of teleosts (denoted by red/dotted lines). (PAMPs- pathogen-associated molecular patterns, PGN-peptidoglycan, MDP- muramyl dipeptide, ERK- extracellular signal-regulated kinase, RIPK- receptor interacting protein kinase, ASC- apoptosis-associated speck-like protein containing a CARD, AP-1- activator protein-1, NEMO- NF-kB essential modulator, NF-kB- nuclear factor kappa-light-chain-enhancer of activated B cells, TAK1- TGFb-activated kinase 1, GRIM-19- gene associated with retinoid-IFN-induced mortality, MAVS-mitochondrial antiviral signaling protein, MDA5- melanoma differentiation-associated protein 5, RIG-1- retinoid acid -inducible gene I, IRF- interferon regulatory factor, IFN- interferon).

Figure 4

Signaling pathways of NLRC3, NLRC5. In mammals, NLC3 inhibit TLR signaling via TRAF6, type I/II/III IFN response and immune pathways viz. STING, NF-kB, ERK, P13K/AKT/mTOR, TCR. It also competes with ASC to bind with pro-caspase-1 and interferes with the assembly of NLRP3 inflammasome. In addition to generally inducing MHC class I genes, NLRC5 inhibit RIG-1, MDA5 and type I IFN as well modulate immune pathways such as NF-kB, JAK2/STAT3, AKT/VEGF-A, PI3/AKT and IFN-1 pathway. In teleosts, NLRC3/C3L modulate cytokine expression while (possibly) interacting with RIPK (denoted by red/dotted lines). NLRC3L is reported to inhibit NOD1-mediated downstream signaling pathways (denoted by red line). NLRC3 is also reported to interact with ASC, however the downstream signaling remains elusive. (STING- stimulator of interferon genes, NF-kB- nuclear factor kappa-light-chain-enhancer of activated B cells, ERK- extracellular signal- regulated kinase, P13K- phosphatidylinositol-3-kinase, AKT- Protein kinase B, mTOR- mammalian target of rapamycin, TCR- T cell receptor, ASC- apoptosis-associated speck-like protein containing a CARD, IFN- interferon, MDA5- melanoma differentiation-associated protein 5, RIG-1- retinoid acid -inducible gene I, JAK/STAT- janus kinase/signal transducers and activators of transcription, VEGF-A- Vascular endothelial growth factor A, MHC- major histocompatibility complex, RIPK- receptor interacting protein kinase).

Figure 5

Signaling pathways of NLRX1. In response to PAMPs, NLRX1 interacts with UQCRC2 leading to ROS production and induction of NF-kB and JNK pathways. It also negatively regulates MAVS-mediated RLR signaling and TRAF6-NF-kB signaling. In teleosts, NLRX1 inhibit gene expression of IRFs and IFNs (denoted by red lines). (UQCRC2- Ubiquinol-Cytochrome C Reductase Core Protein 2, RLH-RIG-1-like helicases, MAVS- mitochondrial antiviral signaling protein, TRAF-6-Tumor necrosis factor receptor (TNFR)-associated factor 6, FN- interferon).

Figure 6

Signaling pathways of inflammasome forming NLRs. PAMPs interact with inflammasome forming NLRs (NAIP-NLRC4, NLRP1, NLRP3) as well as non-inflammasome forming NLRs such as NLRP6 which then activates procaspase-1 leading to inflammatory response. In non-canonical pathway, NAIP-NLRC4 interact with caspase-8 whereas NLRP6 and NLRP12 interact with caspase-4,5,11 to induce pyroptosis. In addition, in teleost, NLRP3rel has also been shown to follow similar inflammasome signaling pathways (denoted in red lines). (LTA- lipoteichoic acid, ATP- adenosine triphosphate, S. aureus- Staphylococcus aureus NAIP- neuronal apoptosis inhibitory protein, ASC- apoptosis-associated speck-like protein containing a CARD).