SurveyNOD-like receptors and the innate immune system: Coping with danger, damage and death
Introduction
Protection of an organism against harmful internal and external insults relies on the ability of the innate immune system to discriminate between what is dangerous and what is not. Innocuous signals are largely normal host proteins and commensal bacteria that have induced tolerance, whereas danger signals include pathogens, host-derived signals of cellular stress or danger, and environmental insults. Such threats are recognized by a number of germline-encoded danger-sensing receptors (DSRs) that detect conserved pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The main objective of this ‘first line of defense’ is to mount a rapid but non-specific response that keeps the challenge in check. In addition, the innate immune response also regulates and directs the activation of the more specific adaptive immune system.
Hematopoietic cells, including macrophages, dendritic cells and neutrophils, as well as non-hematopoietic cells such as epithelial cells, contribute to this host-defense system by expressing DSRs. Different DSRs have been classified into families according to their subcellular localization, molecular structure, and recognition repertoire. Members of the Toll-like receptor (TLR) family and C-type lectin receptor (CLR) family are transmembrane receptors that line the plasma and endosomal membranes to survey the extracellular environment and the endosomes for the presence of PAMPs and DAMPs [1], [2]. Intracellular monitoring, which is critical when insults evade extracellular surveillance, is performed by the broad-spectrum PAMP- and DAMP-sensing nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the viral RNA-sensing RIG-like helicase receptors (RLRs), and the cytosolic DNA sensors, RNA polymerase III, DAI, and absent-in-melanoma 2 (AIM2) [3], [4], [5]. When these receptors bind their agonists, they trigger an innate immune response by engaging specific signaling cascades. These signaling cascades lead to the production of certain cytokines and chemokines by activating transcription factors such as NF-κB, AP-1, Elk-1, ATF2, p53 and members of the interferon regulatory factor (IRF) family [6], [7], [8]. Chemokines, such as IL-8, MCP-1 and KC, attract other immune-regulatory cells, including neutrophils, monocytes and leukocytes, to the endangered area, while cytokines such as interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF) determine how the cell responds.
This review focuses on the NLR family, whose members contribute to innate immunity by participating in multiple cellular processes, including inflammasome assembly to activate procapase-1 for the processing of IL-1β and IL-18 [3], caspase-1 dependent pyroptotic cell death [9], activation of NF-κB and MAPK signaling pathways to induce transcription of cytokines and chemokines [10], autophagy [11], [12], and control of type I interferon (IFN) signaling [13], [14], [15]. So far, in silico work has identified 22 human and 34 mouse NLR members [16], [17]. The defining feature of NLRs is the presence of a NACHT domain (domain present in NAIP, CIITA, HET-E, and TP-1), which is generally followed by a series of leucine-rich repeats (LRRs) [18] (Fig. 1). As a member of the AAA+ superfamily of nucleotide-binding and oligomerization domains, the NACHT domain mediates NLR oligomerization, whereas the LRRs form the sensing module [19]. In addition, apart from NLRX1, all NLRs contain an N-terminal effector module, which is used to classify them into four subfamilies [18]. The NLRA subfamily contains only the founder NLR, CIITA, because it is the only NLR with an acidic transactivation domain (Fig. 1). This domain plays an essential role in the transcriptional regulation of MHC Class II genes [20]. Moreover, mutations in CIITA predispose patients to immunological disorders, such as the bare lymphocyte syndrome [21]. All other NLR proteins contain a homotypic protein–protein interaction module at their N-terminus that enables them to recruit important signal transduction molecules after ligand sensing. These homotypic interaction modules are either a baculovirus inhibitor repeat domain (BIR), a caspase recruitment domain (CARD) or a pyrin domain (PYD), which define the subfamilies as NLRB, NLRC and NLRP, respectively (Fig. 1). Looking at the human NLRs, the NLRB subfamily contains one member, NAIP (BIRC3); the NLRC subfamily has six members, NOD1, NOD2, NLRC3, NLRC4 (IPAF), NLRC5 and NLRX1; and the NLRP subfamily has 14 members, NLRP1 to NLRP14 (Fig. 1). However, the NLRC subfamily appears to be more complex. NLRC3 and NLRC5 are likely to encode a homotypic interaction module belonging to the death-fold superfamily, though it has not been firmly established whether it is a CARD domain or another death-fold domain, death domain (DD), death effector domain (DED) or PYD. NLRX1 is included in the NLRC subfamily because it has a CARD-related ‘X’ domain [22]. Finally, the interaction module lacking CIITA contains a CARD-like domain in the isoform expressed in dendritic cells [23].
The importance of the NLR family to the innate immune system is further supported by the apparent evolutionary conservation of the NLR family. Indeed, to deal with pathogens and environmental insults, plant genomes contain many disease resistance genes, the so-called R genes, which encode a set of proteins containing nucleotide binding leucine-rich repeats (NB-LRR) [24].
Section snippets
Biological outcomes of procaspase-1 activity
Procaspase-1 is the founder member of an evolutionarily conserved family of cysteine-dependent aspartate-specific proteases named caspases, which are chiefly known for their involvement in the initiation and execution of apoptosis [25], [26]. However, procaspase-1 is not a pro-apoptotic protease. Instead, it plays an important role in innate immunity by processing and activating the pro-inflammatory cytokines IL-1β and IL-18, as well as by promoting an inflammatory type of cell death called
Role of NOD1 and NOD2 in health and disease
Initially, NOD1 (NLRC1) and NOD2 (NLRC2), two of the first characterized members of the NLR family, were reported to be intracellular sensors for LPS [262], [263], [264]. However, the LPS preparations used in those studies appeared to have been contaminated with other bacterial products. Subsequently, NOD1 and NOD2 were shown to recognize two different fragments of the bacterial cell wall component peptidoglycan: ieDAP (γ-d-glutamyl-meso-diaminopimelic acid) and MDP (MurNAc-L-Ala-d-isoGln),
Conclusions and perspectives
Since the discovery of the NLRP1 inflammasome and the NOD proteins a decade ago, a wealth of knowledge has been gained on the contribution of the NLR-family to innate immunity [59], [285], [286]. Of particular value are the elucidation of the underlying molecular mechanisms and the association of these proteins to an increasing number of pathologies, including gout, type II diabetes, atherosclerosis, silicosis, Alzheimer's disease, CD, CAPS, and a diverse range of infections. CAPS patients are
Kristof Kersse obtained his PhD in Biotechnology in 2011 at the Faculty of Sciences, Ghent University and the Flanders Institute for Biotechnology (VIB), Belgium. In his doctoral thesis he studied the role of the CARD domain of caspase-1 and the inflammasome complexes in the innate immune system. At the moment, he is a postdoctoral research fellow with Peter Vandenabeele at Ghent University and VIB, Belgium. His work focuses on the elucidation of the molecular mechanisms regulating
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Kristof Kersse obtained his PhD in Biotechnology in 2011 at the Faculty of Sciences, Ghent University and the Flanders Institute for Biotechnology (VIB), Belgium. In his doctoral thesis he studied the role of the CARD domain of caspase-1 and the inflammasome complexes in the innate immune system. At the moment, he is a postdoctoral research fellow with Peter Vandenabeele at Ghent University and VIB, Belgium. His work focuses on the elucidation of the molecular mechanisms regulating caspase-1-dependent pyroptosis in comparison with apoptotic and necrotic cell death.
Mathieu JM Bertrand is Tenure Track member of the Faculty of Sciences, Ghent University, and postdoctoral researcher at the Flanders Institute for Biotechnology (VIB), Belgium. He obtained his PhD in Biomedical Sciences in 2005 at Namur University, Belgium. He did postdoctoral studies with Phil Barker at McGill University, Canada, and with Peter Vandenabeele at Ghent University and VIB, Belgium. His main research interests consist in the elucidation of the molecular mechanisms of non-degradative ubiquitination in cancer, cell death and inflammation. Now he focuses on these topics during ER stress.
Mohamed Lamkanfi is member of the medical faculty at the Ghent University and the Flanders Institute for Biotechnology (VIB), Belgium. He obtained his PhD in Biochemistry in 2004 working on inflammatory caspases in the lab of Peter Vandenabeele at Ghent University and VIB. He did postdoctoral studies with Gabriel Nuñez at the University of Michigan, Ann Arbor, USA, and with Vishva Dixit at Genentech, San Francisco, California, USA. His group studies the role of NOD-like receptors and inflammasomes in immune signaling.
Peter Vandenabeele is full professor at the Faculty of Sciences of the Ghent University, president of the Biochemistry and Biotechnology program at the Faculty of Sciences and group leader at the Flanders Institute for Biotechnology (VIB). He obtained his PhD in Biology at the Ghent University with Walter Fiers as promotor. He is an expert in cell death mechanisms, more precisely the role of caspases and RIP kinases.
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These authors share senior authorship.