Trends in Biochemical Sciences
ReviewNLR activation takes a direct route
Section snippets
NLR activation and signalling in innate immunity
The basics of the innate immune response are conserved throughout evolution. Germ-line-encoded proteins known as pattern recognition receptors (PRRs) function by recognising ‘danger signals’ and then initiating a protective innate immune response. Danger signals can be derived from both exogenous and endogenous sources and include: pathogen-derived proteins, lipids, nucleic acids, and polysaccharides; crystalline materials; high levels of ATP; specific host proteins and nucleic acid; and
Do NOD1 and NOD2 interact directly with peptidoglycan fragments?
NOD1 and NOD2 are activated by fragments of peptidoglycan (Figure 1) from the bacterial cell wall. Peptidoglycan fragments containing DAP, found in Gram-negative bacteria [19] and a few Gram-positive bacteria such as Listeria spp. and Bacillus spp. 20, 21, activate NOD1. By contrast, NOD2 responds to MDP, which is found in Gram-positive bacteria, Gram-negative bacteria, and mycobacteria [22]. In fact, mycobacterial N-glycolyl MDP is the most potent NOD2 agonist identified to date [23]. Early
The LRR domain of NLRX1 directly binds RNA ligands
Nucleic acid agonists are detected predominantly by members of the TLR, RLR, and ALR receptor families, and there is clear structural evidence for the direct binding of the nucleic acid ligand to these receptors. For example, crystal structures have been resolved for TLR3 bound to its double-stranded (ds)RNA ligand [27], for RIG-I and various RNA ligands 28, 29, 30, 31, 32, and the HIN (hemopoietic interferon-inducible nuclear protein) 200 domains of both AIM2 and IFI (interferon gamma
Activation of the NLRC4/NAIP inflammasome requires direct interaction with bacterial proteins
NLRC4 and NAIP form an inflammasome (Figure 1) in response to flagellin and components of bacterial type III secretion systems (T3SSs), such as the protein PrgJ (pathogenicity 1 island effector protein J) from Salmonella spp. 36, 37, 38. Recognition of T3SS proteins depends on C-terminal peptide sequences similar to regions of flagellin, mutation of which impairs NLRC4/NAIP activation [38]. Originally, NLRC4 was believed to be responsible for ligand detection 36, 37. More recently, the Shao and
Cellular stresses activate NLRP3. Is the activating ligand of exogenous or endogenous origin?
NLRP3 is activated in response to an overwhelming array of stimuli that cause various biochemical responses in the cell and disrupt the homeostatic balance (Table 1) [3]. These include potassium efflux, membrane permeabilisation, lysosomal leakage, mitochondrial dysfunction, and reactive oxygen species (ROS) (Figure 1 and Table 1) [3]. The importance of ROS in NLRP3 activation is currently under debate because many of the pharmacological ROS inhibitors also impair NLRP3 priming [44]. It seems
NLRC3, NLRC5, NLRP6, and NLRP10: NLRs as immune regulators
Not all NLRs described to date are proinflammatory and do not therefore require an activatory ligand. NLRC3 and NLRP6 antagonise inflammatory signalling 56, 57, 58, 59, 60, 61, whereas NLRC5 and NLRP10 appear to regulate transcription of MHC I and development of the adaptive immune response, respectively 62, 63, 64, 65.
NLRC3 inhibits NF-κB activation by TLR signalling pathways through interaction with the downstream signalling adaptor TRAF (tumour necrosis factor receptor-associated factor) 6.
Concluding remarks
Without question our continual desire to understand NLR biology is driving forward innate immune research. It continues to provide a clear picture of the underlying biological events that occur during the detection of, and response to, cellular damage of both an endogenous and exogenous nature. It also continues to enhance our understanding of disease progression, genetic susceptibility to disease, and the interplay between the innate and adaptive arms of the immune response. Despite the rapid
Acknowledgements
The work in the laboratory of T.P.M. is funded by The Wellcome Trust (WT0805090MA).
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Mechanisms of NLRP3 inflammasome activation and the development of peptide inhibitors
2023, Cytokine and Growth Factor ReviewsNBS-LRR genes-Plant health sentinels: Structure, roles, evolution and biotechnological applications
2019, Applied Plant Biotechnology for Improving Resistance to Biotic StressMulti-step regulation of innate immune signaling by Kaposi's sarcoma-associated herpesvirus
2015, Virus ResearchCitation Excerpt :NLRs comprise a family of more than 22 members of cytoplasmic receptor proteins that are characterized by a conserved NOD motif (Harton et al., 2002; Lupfer and Kanneganti, 2013). Another feature of the NLR family is the presence of a LRR domain with the proposed function of detecting PAMPs, thus leading to NLR activation (Monie, 2013). NLRs can be divided into 4 subfamilies, based on different N-terminal effector domains: caspase recruitment domain (CARD), pyrin domain (PYD), baculoviral inhibitor of apoptosis repeat (BIR) domain, and the transactivation domain.
High throughput screening identifies ATP-competitive inhibitors of the NLRP1 inflammasome
2015, Bioorganic and Medicinal Chemistry LettersThe surprisingly complex immune gene repertoire of a simple sponge, exemplified by the NLR genes: A capacity for specificity?
2015, Developmental and Comparative ImmunologyCitation Excerpt :Phylogenetic analysis instead reveals discrete clades characterised by the nature of their C-terminal LRR domain (Yuen et al., 2014). This is significant because, based on their function in other protein contexts, combined with limited empirical evidence from some vertebrate NLRs (Monie, 2013), it is thought that LRRs are the part of the protein that interacts directly with bacterial ligands. Two clades of AqNLRs together contain thirteen (nine of which are tripartite) NLRs that all are characterised by “standard” LRRs easily recognisable by the sequenced-based Pfam LRR clan HMMs (CL0022) (Yuen et al., 2014).
Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators
2014, FEBS LettersCitation Excerpt :NOD2 is a member of the cytosolic NLR (nucleotide-binding, leucine-rich repeat containing) family of pattern recognition receptors [7]. NOD2 is activated by the peptidoglycan component muramyl dipeptide, following which NOD2 engages the adaptor receptor interacting protein 2 (RIP2) to initiate pro-inflammatory signalling pathways involving nuclear factor kappa B (NF-κB) and stress kinases [7–9]. NOD2 plays an important role in the response to bacterial infection, including the activation of autophagy.