Pattern Recognition Receptors and Cancer : Is There Any Role of Inherited Variation ?

The group of the pattern recognition receptors (PRRs) includes families of Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs) and RIG-I-like receptors (RLRs). The summary of the most modern conceptual data about members of these families and about their structure and functions can be obtained from the recent comprehensive reviews (Elinav et al., 2011; Kawai and Akira, 2011; Osorio and Reis E Sousa, 2011; Loo and Gale, 2011), and the schemes of their signaling are presented in Figures 1-2.

on the ER membrane (in the resting state) or on the endosomal/lysosomal membrane (after ligand stimulation and trafficking).According to the known data about their structure (Hashimoto et al., 1988), TLRs belong to type I transmembrane glycoproteins and contain three major domains (Matsushima et al., 2007).The ectodomain is oriented towards the extracellular space or cytoplasm (depending on receptor localization) and contains multiple (16-28) leucine-rich repeats (LRRs) that harbor 24-29 amino acids and may contain two types of motifs: typical (T) motifs (LxxLxLxxNxLxxLxxxxF/LxxLxx) and bacterial (S) motifs (LxxLxLxxNxLxxLPx(x)LPxx) (Bell et al., 2003;Matsushima et al., 2007).LRR modules fold into the parallel -sheets that bend into a concave surface, forming one or two distinct horseshoe structures determining the unique horseshoe shape of TLRs (Matsushima et al., 2007).LRR hydrophobic residues are packed within the interior of ectodomain structure, forming a ligand-binding hydrophobic pocket (Bell et al., 2003(Bell et al., , 2006;;Kim et al., 2007;Liu et al., 2008).In addition, C-terminal LRRs may control the receptor dimerization and the signal transmission (Takada et al., 2008).The single-spanning transmembrane domain is homologous to IL-1R analog and anchors the receptor in the correct orientation on cell membrane (Huyton et al., 2007;Medzhitov et al., 1997).Third, the cytoplasmic TLR domain (toll/interleukin-1 receptor domain, TIR domain) is usually composed of approximately 150 amino acid residues (Jin and Lee, 2008) and dimerizes after the ligand-ectodomain interaction (TLR ligands are presented in Table 1) and respective alterations in the receptor conformation, triggering the recruitment of the adaptor proteins (MyD88, TIRAP/MAL, TRIF, TRAM, SARM) to initiate the specific signaling pathway of the immune response stimulation (Jin and Lee, 2008;O'Neill and Bowie, 2007).It is important that all TLRs form hetero-or homodimers, and this feature may facilitate the dimerization of the cytoplasmic domain.All adaptors indicated above contain TIR domains, and interactions between such domains of receptor and adaptor are key for the successful signaling (Palsson-McDermott and O'Neill, 2007).The process of TLR signaling is mediated by a number of other adaptor proteins and, finally, leads to activation of NF-κB (Yamamoto et al., 2004), MAPK (Yamamoto et al., 2004), JNK (Takeuchi and Akira, 2001), IRF1, IRF3, IRF5, IRF7 and IRF8 (Honda and Taniguchi, 2006) that move into the nucleus and directly or indirectly control the transcriptional activity of the genes encoding various proinflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, IL-13, IL-23, IL-27, MIP-1, MCP-1, RANTES, SOCS, IP-10, GM-CSF, TNF-, IFN-, IFN-, IFN-and IFN-inducible proteins (Chang, 2010;Wong et al., 2011;Zhu and Mohan, 2010).

Member of TLR family
Exogenous ligand Endogenous ligand TLR1 (form heterodimers with TLR2)   (Chen et al., 2009).First, the C-terminal domain, contains multiple leucine-rich repeats (LRRs), directly recognizing exogenous and endogenous ligands (Kumar et al., 2009).The second, central, nucleotide-binding oligomerization domain (NOD) has intrinsic ATPase activity and is responsible for the self-oligomerization and the formation of a complex after the ligand binding for the activation and recruitment of downstream signaling proteins (Kumar et al., 2009).These two domains are common for all known NLRs (Chen et al., 2009).Third, variable, the N-terminal protein-protein interaction domain, may represent a caspase recruitment domain (CARD), death effector domain (DED), pyrin domain (PYD), acidic transactivating domain, or baculovirus inhibitor of apoptosis protein repeat domain (BIR domain) (Kanneganti et al., 2007).The most investigated of NLRs are NOD1/CARD4 and NOD2/CARD15.Both NOD1/CARD4 and NOD2/CARD15 recognize the components of bacteria cell wall: ligands of NOD1/CARD4 are -D-glutamyl-m-diaminopimelic acid (iE-DAP) and its synthetic derivatives (particularly having hydrophobic acyl residues) (Chamaillard et al., 2003;Girardin et al., 2003), and the ligand of NOD2/CARD15 is muramyl dipeptide (MDP) (Girardin et al., 2003).These compounds are the components of peptidoglycan (PGN).They can enter the cytosol through the pores formed as a result of bacterial toxin exposure (Ratner et al., 2007), via action of the pathogen secretion systems (Ratner et al., 2007), by endocytosis (Marina-Garcia et al., 2008) or by work of transporters (Ismair et al., 2006), and they can be released in the cytosol of infected cells during a bacterial cell division or from lysosomes where PGN of phagocytosed bacteria is degraded (Shaw et al., 2010).Until the ligand binding, LRR-containing C-terminal domain of NOD1/CARD4 and NOD2/CARD15 prevents the activation of the central domain (NOD) and its further oligomerization (Faustin et al., 2007); ligand binding causes the conformational alterations in the C-terminal region that, in turn, lead to self-oligomerization of the central domain and to the further activation of N-terminal domain (CARD) that recruits and activates specific adaptor proteins, initiating NOD signaling pathways.Such initiation results in the activation of various transcription factors and, consequently, in the production of proinflammatory mediators (Inohara et al., 1999;Ogura et al., 2001).
Although CLRs and RLRs are investigated relatively less than TLRs and NLRs, it is known that they recognize bacterial, viral, fungal, protozoan, and helminth PAMPs as TLRs and NLRs (Table 2), initiating an immune response against them through their specific signaling pathways (as their structure is not so clear as in the case with signaling pathways of TLRs and NLRs, it will be precisely depicted only in the following years).It is crucially important to note that in many steps signaling pathways of all classes of PRRs may intersect, making possible the crosstalk between them.The receptors constituting families of PRRs are united by two general features.Firstly, they directly recognize common antigen determinants of virtually all classes of pathogens (so-called pathogen-associated molecular patterns, or simply PAMPs) and initiate immune response against them via specific intracellular signaling pathways.Secondly, they recognize endogenous ligands (since they are usually released during cell stress, they are called damage-associated molecular patterns, DAMPs), and, consequently, PRRmediated immune response can be activated without influence of infectious agents.Therefore, PRRs may also initiate the development of aseptic inflammation caused by physical factors such as mechanical pressure, thermal damage, ionizing and non-ionizing radiation, or chemical factors (for instance, acidic damage, alkaline damage, exposure to chemical war gases, croton oil or turpentine, exposure to allergens, liberation of toxic substances during tumor disintegration, aseptic necrosis, internal bleeding, haemolysis, autoimmune processes etc.).It may promote the further progression of inflammation or, on the contrary, prevent the hazardous infectious complications (the combination of these two effects may also be true).The final outcome of PRR working is an enhanced production of the many proinflammatory cytokines participating in a plenty of immune system processes.Expression of PRRs on different levels (transcriptomic or proteomic) was detected in a lot of cells and organs, so it gave an evidence that these receptors control many elements of the complex machinery of human immune system: they allow epithelium and endothelium to defend against infectious agents on their own, they mediate the activation of adaptive immune response by antigen-presenting cells and Thelpers, they stimulate expression of cell adhesion molecules for leukocyte rolling and for other processes of inflammation development, and, finally, they contribute to phagocytosis efficacy (Chang, 2010).As a consequence of all written above, pattern recognition receptors play the key role in realization of innate and adaptive immune response.In addition, many PRRs have a number of other vital functions apart from participation in the immune response realization: they may regulate various aspects of cell proliferation, survival, apoptosis, autophagy, reactive oxygen species generation, pyroptosis, angiogenesis and, consequently, of tissue remodeling and repair (Brown et al., 2007;Fukata et al., 2006;Kim et al., 2007;Rakoff-Nahoum and Medzhitov, 2008).

Receptor
The fundamental character and diversity of PRR functions have led to amazingly rapid research in this field, and such investigations are very perspective for medicine as immune system plays a key role in vast majority if not all human diseases, and the process of discovering new aspects of the immune system functioning is rapidly ongoing.There is a plethora of papers analyzing the significance of PRRs in various diseases.One of the most actively exploring fields in PRR biology is their role in cancer aetiopathogenesis.Not surprisingly, it is (as well as tumor immunology in general) a hot spot in cancer biology as well.

The position of pattern recognition receptors in cancer biology
Since PRRs mediate immune response inducing by many immunoadjuvants (Okamoto and Sato, 2003;Seya, 2003), and many of them regulate immune response against potentially carcinogenic infectious agents (Helicobacter pylori, EBV, HPV, HHV-8/KSHV, CMV, Mycobacterium tuberculosis, Streptococcus pneumoniae, enteropathogenic Escherichia coli, Shigella flexneri, Salmonella typhimurium, Borrelia burgdorferi, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, Campylobacter jejuni, Candida spp., Schistosoma mansoni, Paracoccidioides brasiliensis, Histoplasma capsulatum etc.), it seems to be possible to stimulate anti-tumor immunity through their enhanced activation.This hypothesis, originally developed for the TLRs, should be also true for the all PRRs as well (Killeen and Wang, 2006;Tsan, 2006).According to this suggestion, a reinforced PRR activation may protect from infectious agents and prevent, inhibit, or block carcinogenesis whilst disrupted functioning of these PRRs may allow infectious agents or tumor cells to avoid recognition by immune system and, consequently, not to be eliminated.At the same time, such PRR activation may promote carcinogenesis, creating a proinflammatory microenvironment (via action of respective cytokines) that is favorable for the tumor progression and chemoresistance development (Chen, 2007).It may also result in immunosuppression caused by chronic inflammation (Tsan, 2006).Chronic inflammation may promote the development of cervical, endometrial, ovarian, breast, prostate, testicular, nasopharyngeal, Pattern Recognition Receptors and Cancer: Is There Any Role of Inherited Variation?89 lung, esophageal, gastric, colorectal, liver, pancreatic, gallbladder, kidney, bladder, lymphatic malignancies, and feasibly several other cancer types (Kinlen, 2004;Okamoto and Sato, 2003).In this case, on the contrary, lower PRR activity should minimize the effects of chronic inflammation such as enhancement of cancer initiation and promotion/progression and, consequently, decrease the probability of tumor development.So, the situation resembles a double-edged sword.The ideal variant, possibly, is the «golden mean» -the balance between low and high PRR activity.This hypothesis, developed for PRRs, may also be successfully projected on PRR intracellular signaling pathways -if their elements are overexpressed/constantly activated, it may lead to similar consequences as enhanced PRR activation.On the other hand, if the members of PRR pathways are underexpressed/inactivated/unable to do their work at the right time in the right place, it may result in the same effects that arise after decreased PRR activity, and the analogical «golden mean» in functioning of all genes encoding proteins constituting PRR signaling pathways will be the optimal variant.

Structural genomic variation and its relevance to cancer
The novel approaches in healthcare move towards the model of "personalized medicine".Advances in the healthcare service grow annually as well as their social relevance.Diagnostic tests and target therapy have become a part of our life.However, in spite of the neoteric improvements of the screening and treatment modalities, the prognosis of patients with many diseases including cancer remains poor.Thus, modern molecular biology and medicine are concerned on the developing of more and more new genomic markers that possess predictive, therapeutic, or prognostic significance.Several markers may evaluate predisposition of any person to one or another disease with a certain degree of accuracy based on the results of a simple blood test.The widespread application of these tests can reveal the risk groups in populations, and thereafter, the complex of preventive measures among the risk group subjects may be conducted.Moreover, above-mentioned genomic markers can be identified in the perinatal period, so the choice between "include" or "not to include" in the risk group on their basis can be made maximally early, and, consequently, the preventive measures can have the greatest efficacy.As a result, the integrative systems of predictive genomic markers, defined once, will allow to create the programs of cancer prevention based on them and will permit next generations to be informed and forewarned about their risks and predispositions to certain diseases.
Thereby, the discovery and development of predictive, therapeutic, or prognostic markers is the primary problem of biomedicine at the present time.However, the critical barrier for progress in this field is that it is not always easy to find an effective genomic marker that is exactly associated with a particular disease.One of the most widespread and important markers is the type of genomic markers called single nucleotide polymorphisms (SNPs).They represent a variation in the DNA sequence, when a single nucleotide differs between members of a biological species or paired chromosomes in an individual.The finishing of Human Genome Project and the widespread distribution of genotyping technologies have led to the enormous number of studies devoted to the association of the inherited gene polymorphisms with various diseases.The SNPs may result in amino acid substitutions altering protein function or splicing, and they can also change structure of enhancer sequences during splicing (Lamba et al., 2003) or affect mRNA stability (Tierney and Medcalf, 2001).SNPs may also alter transcription factor binding motifs, changing the efficacy of enhancer or repressor elements (Thomas et al., 2006), and they can alter the structure of translation initiation codons that may lead to the downregulation of wild-type transcript (Zysow et al., 1995).Gene polymorphisms located in the leucine-rich repeats constituting ectodomain of PRRs may affect the ability of receptor to bind pathogens they normally recognize (Bell et al., 2003), SNPs in the transmembrane domain can lead to the defects of the intracellular receptor transport that do not allow to locate a receptor on the membrane (Johnson et al., 2007), and, finally, the polymorphisms in the internal domain may result in the altered interaction with the adaptor proteins or in the disrupted dimerization.So, inherited SNPs of the genes encoding PRRs may alter PRR expression and activity, modulating cancer risk and, possibly, influencing on various features of the cancer progression.The same statement should be true for the genes encoding proteins of PRR signaling pathways.
On the basis of the fundamental and epidemiological studies, it is possible to specify the two fundamental mechanisms for the modulation of cancer risk by the polymorphisms of the genes encoding PRRs and proteins of PRR pathways.The first of them is the impairment of the immune response to the certain pathogens (it can be bacteria, viruses, fungi, protozoan, and helminths) that increase the risk of the potentially carcinogenic infection and promote its development along with further chronic persistence.The second mechanism is an increase of production of proinflammatory cytokines after the binding of the ligand (exogenous or endogenous) that create a condition of carcinogenic chronic inflammation.

Relevant malignancies: the first dimension of investigation
There is a variety of cancer types that can be associated with the inherited alterations in the genes encoding PRRs and proteins of PRR signaling pathways: Brain tumors (the alteration of the immune response to CMV and other viruses).

Selection of valuable polymorphisms: the second dimension of investigation
It is important to remember that there are two main components determining the importance of the SNP in the programs of cancer prevention based on genomic risk markers: the value of odds ratio (OR) between cases and controls (as in the whole population as in subgroups) and the prevalence of the polymorphism in population, and they both may vary in different geographic regions.It is desirable to develop not the one general program, but a number of the individual programs for the different countries/populations/environmental conditions.At the moment, it is possible only to recommend a list of polymorphisms for the further investigation since only small number of studies with perfect design was carried out.The list of relevant polymorphisms that can be admitted as the most perspective for the further oncogenomic investigations may be created according to the following rules: Gene polymorphism may be included into the short list for the further oncogenomic studies if:


The SNP leads to the substantial functional consequences on the molecular level (for instance, it strongly affects transcription, splicing, translation, stability and transport of pre-mRNA, mRNA, non-coding RNA or protein encoding by the gene, or it noticeably influences signaling of synthesized protein);  It is associated with risk of cancer in the population studies;  It has any functional consequences on the molecular level and it is strongly (threshold OR value may be individual for each cancer type) associated with condition that significantly increases risk of cancer.


The gene polymorphism can be also included into the extended list if:  It is characterized by more subtle functional alterations in the gene that, however, still result in qualitative or quantitative alterations of the encoding protein (or non-coding RNA);  It is associated only with condition that substantially increases risk of cancer but not with risk of cancer.
One question may immediately arise: how to distinguish «substantial» and «more subtle» functional changes on the molecular level?It seems to be difficult to answer only on the basis of general principles of molecular biology since for one gene even the smallest alteration in its structure may lead to critical consequences, for another one converse statement can be true, and the effect also greatly depends on the position of the polymorphism.Therefore, an assessment of power of functional alteration should be individual for each gene, and although conclusions obtained in various investigations may differ, these discrepancies would not distort the general picture: if the polymorphism has «serious» functional consequences according to the results of one research, it definitely should be added into the short list until these conclusions will not be subverted.In any case, the general value of creation of such short and extended lists of the prescriptive polymorphisms seems to overcome difficulties related to these complications.It is important that many polymorphisms can be simply in the linkage disequilibrium with truly functional variants, and fundamental investigations are needed to determine are they only markers of association or indeed causal variants.All polymorphisms that are only in the linkage disequilibrium with functional ones should be excluded from both lists.

Gene
Table 4.The extended list of the polymorphisms of the genes encoding PRRs and proteins of their signaling pathways promising for the further oncogenomic studies.

How to organize the study: the third dimension of investigation
The drawing-up of a rigorous study protocol is the crucial moment in the molecular epidemiology, and in some cases the complexity of the research is considerable.Even if the investigation has a valuable aim, sufficient funding and is carried out in an excellent laboratory, errors in the study design may lead to the misrepresentation of the research results and, hence, to the reduction of their usefulness.All moments that can distort the study accuracy should be taken into account, and certain, the most relevant of them, are discussed below.Obviously, the methods of the sample collection, DNA extraction, and PCR conduction should be reliable enough.Modern methods such as automated DNA extraction, real-time PCR, and pyrosequencing should be used, although traditional methods such as allele-specific PCR with visualization in the agarose gel can be exploited as well, and their application definitely will be continued for the next decade.Anyway, automated methods should be of choice compared to methods where a subjective factor is substantial and can influence the results.The improvement of existing technologies and the development of new ones may elevate the accuracy of DNA extraction and PCR, leading to increase of validity of the results and, consequently, to the further progress in the field.
Other important aspects of the study design also should be considered.To differentiate the impact of the chronic inflammatory conditions from the contribution of the other mechanisms in the association of the polymorphisms of the genes encoding PRRs and proteins of PRR signaling pathways with cancer risk, the stratification of cases and controls by infectious agent status and chronic inflammation status should be mandatory in the further studies devoted to this problem.The sample size should be sufficient, and it depends on the frequency of target polymorphism -if it is high, sample size can be less than in the studies where target SNP frequency is low.There is also a lack of studies investigating functional consequences of the polymorphisms of the genes encoding PRRs and proteins of PRR pathways on molecular level (for instance, alterations in the promoter activity, in the gene expression on the transcriptomic and proteomic levels, in stability or/and localization of the non-coding RNA, pre-mRNA, mRNA and protein inside the cell, in protein structure and functions, etc.).It is important since many polymorphisms can be simply in linkage disequilibrium with the other, truly functional variants, and thus such fundamental studies are necessary to clarify their role (are they only markers of association or indeed causal variants?).In addition, in certain populations replication studies should be conducted to prove results that were obtained in prime investigations, particularly if the sample size was not large.
There are certain disparities in different population studies investigating the association of the polymorphisms of the genes encoding PRRs and proteins of their signaling pathways with various aspects of cancer development.General reasons for these discrepancies may include confounding host, bacterial, or environmental factors in different ethnicities modulating the penetrance of the variant allele and affecting risk of condition increasing cancer risk (such as autoimmune diseases, precancerous gastric lesions, tuberculosis, recurrent pneumonia etc.), different bacterial impact in aetiology of such conditions in different populations (that will be reflected in different features of PRR-mediated immune response because of specific PRR-ligand interaction), differences in the sample size, in age/gender/BMI/ethnicity/TNM stage/other clinicopathological characteristics between the study samples, in the prevalence of infectious agent (e.g.HP or EBV) in case and control groups, differences in diagnostics, stratification, genotyping methods, and chance.In addition, certain studies in which negative results were obtained could never been published (so-called file drawer effect) that may create a significant bias and distort a picture that we can observe at the moment.Unfortunately, although some genome-wide association studies (GWAS) relevant to the discussing problem were performed, it is usually not possible to compare them with the non-GWAS on the same cancer type since there are no non-GWAS investigating association of the same SNPs with similar malignancies.It may be feasible in future when the number of studies devoted to this issue will be enough for correct comparative analysis.

Hot spots in the field
The most intriguing moments in the problem of the association of inherited structural variation in the genes encoding PRRs and proteins of PRR signaling pathways with features of cancer development are:  Are SNPs in the genes encoding PRRs or proteins of PRR signaling pathways associated with the features of cancer progression or only with cancer risk?Existing studies have shown controversial results, and the results of most of them allow to suggest that there is no or weak correlation between such polymorphisms and peculiarities of cancer progression.


Are the polymorphisms of the genes encoding CLRs, RLRs, or specific proteins of their signaling pathways associated with risk or progression of cancer?If yes, would be appropriate to include them in the list of polymorphisms using in programs of cancer risk determination and further cancer prevention?As it was shown above, there are some premises to think that these SNPs may be associated with cancer risk.Further fundamental and population studies are necessary to answer this question. Do the polymorphisms of genes encoding PRRs or proteins of PRR signaling pathways (particularly TLRs and TLR pathway) correlate with altered prostate cancer risk or progression?Despite there are some fundamental mechanisms allowing to hypothesize that TLR gene polymorphisms may play a role in prostate cancer aetiology, and a number of comprehensive projects on large samples in various countries was conducted, the reliable associations of these SNPs with prostate cancer risk or with features of prostate cancer progression were not detected, and results vary in different populations.


Are the polymorphisms of the genes of PRR signaling pathways associated with cancer risk or progression to the same extent as polymorphisms of the genes encoding PRRs?It is logical that if SNP of gene encoding specific PRR is associated with risk or progression features of certain malignancies, polymorphisms in the genes encoding specific signaling molecules constituting pathways of this receptor should correlate with similar neoplasms, if they have substantial functional consequences on the molecular level.In contrast to the polymorphisms of the genes encoding TLRs, whose association with solid tumors is a subject of investigation in a lot of genetic association studies, the polymorphisms of the genes encoding proteins of TLR pathway are investigated mostly in relation to leukemia and lymphoma, and their association with epithelial tumors is discovered very poorly.SNPs affecting functional parts of TLR pathway central elements (MyD88, TRIF/TICAM1, TIRP/TRAM/TICAM2, TIRAP/MAL, IRAKs, TRAF3, TRAF6, TAK1, TAB1, TAB2, PKR, IRF3, IRF7) should be the most significant for the oncogenomic studies analyzing this problem.

Fig. 2 .
Fig.2.The signaling of the NOD-like receptor pathway.NLRs usually have three-domain structure(Chen et al., 2009).First, the C-terminal domain, contains multiple leucine-rich repeats (LRRs), directly recognizing exogenous and endogenous ligands(Kumar et al., 2009).The second, central, nucleotide-binding oligomerization domain (NOD) has intrinsic ATPase activity and is responsible for the self-oligomerization and the formation of a complex after the ligand binding for the activation and recruitment of downstream signaling proteins(Kumar et al., 2009).These two domains are common for all known NLRs(Chen et al., 2009).Third, variable, the N-terminal protein-protein interaction domain, may represent a caspase recruitment domain (CARD), death effector domain (DED), pyrin domain (PYD), acidic transactivating domain, or baculovirus inhibitor of apoptosis protein repeat domain (BIR domain)(Kanneganti et al., 2007).The most investigated of NLRs are NOD1/CARD4 and NOD2/CARD15.Both NOD1/CARD4 and NOD2/CARD15 recognize the components of bacteria cell wall: ligands of NOD1/CARD4 are -D-glutamyl-m-diaminopimelic acid (iE-DAP) and its synthetic derivatives (particularly having hydrophobic acyl residues)(Chamaillard et al., 2003; Girardin et al., 2003), and the ligand of NOD2/CARD15 is muramyl dipeptide (MDP)(Girardin et al., 2003).These compounds are the components of peptidoglycan (PGN).They can enter the cytosol through the pores formed as a result of bacterial toxin exposure(Ratner et al., 2007), via action of the pathogen secretion systems(Ratner et al., 2007), by endocytosis(Marina-Garcia et al., 2008)  or by work of transporters(Ismair et al., 2006), and they can be released in the cytosol of infected cells during a bacterial cell division or from lysosomes where PGN of phagocytosed bacteria is degraded(Shaw et al., 2010).Until the ligand binding, LRR-containing C-terminal domain of NOD1/CARD4 and NOD2/CARD15 prevents the activation of the central domain(NOD)

Table 2 .
The ligands of CLRs and RLRs.