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1.
Cell Rep ; 36(8): 109614, 2021 08 24.
Article in English | MEDLINE | ID: mdl-34433041

ABSTRACT

Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1ß. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.


Subject(s)
Carnivora/metabolism , Evolution, Molecular , Inflammasomes/metabolism , Zoonoses/pathology , Animals , Caspase 1/genetics , Caspase 1/metabolism , Caspase 8/metabolism , Caspases, Initiator/genetics , Caspases, Initiator/metabolism , Cell Death , Cell Line , Humans , Interleukin-1beta/metabolism , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , NLR Proteins/genetics , NLR Proteins/metabolism , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Salmonella typhi/pathogenicity , Zoonoses/immunology , Zoonoses/parasitology
2.
Pharmacol Rev ; 67(2): 462-504, 2015.
Article in English | MEDLINE | ID: mdl-25829385

ABSTRACT

Since the discovery of Toll, in the fruit fly Drosophila melanogaster, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future.


Subject(s)
Chronic Disease , Models, Molecular , Mutation , Receptors, Pattern Recognition/genetics , Receptors, Pattern Recognition/metabolism , Signal Transduction , Animals , Cell Membrane/enzymology , Cell Membrane/metabolism , Endosomes/enzymology , Endosomes/metabolism , Humans , Inflammasomes/metabolism , International Agencies , Ligands , Mitochondrial Membranes/enzymology , Mitochondrial Membranes/metabolism , Pharmacology/trends , Pharmacology, Clinical/trends , Protein Isoforms/chemistry , Protein Isoforms/classification , Protein Isoforms/metabolism , Protein Processing, Post-Translational , Receptors, Pattern Recognition/chemistry , Receptors, Pattern Recognition/classification , Societies, Scientific , Terminology as Topic
3.
Open Biol ; 4(12)2014 Dec.
Article in English | MEDLINE | ID: mdl-25520185

ABSTRACT

The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. Downstream effects include the secretion of cytokines such as interleukin 8, the upregulation of pro-interleukin 1ß, the induction of autophagy, the production of antimicrobial peptides and defensins, and contributions to the maintenance of the composition of the intestinal microbiota. Polymorphisms in NOD2 are the cause of the inflammatory disorder Blau syndrome and act as susceptibility factors for the inflammatory bowel condition Crohn's disease. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. However, the functionality of NOD2 is underpinned by its biochemical interactions. Consequently, in this review, we have taken the opportunity to address the more 'basic' elements of NOD2 signalling. In particular, we have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Further, where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. Overall, we provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling.


Subject(s)
Nod2 Signaling Adaptor Protein/metabolism , Signal Transduction , Animals , Arthritis , Autophagy , Cranial Nerve Diseases/genetics , Cranial Nerve Diseases/immunology , Crohn Disease/genetics , Crohn Disease/immunology , Gene Expression Regulation , Humans , Immunity, Innate , Intestinal Mucosa/metabolism , Intestines/immunology , Intestines/microbiology , Nod1 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/chemistry , Nod2 Signaling Adaptor Protein/genetics , Sarcoidosis , Synovitis/genetics , Synovitis/immunology , Uveitis/genetics , Uveitis/immunology
4.
FEBS Lett ; 588(18): 3382-9, 2014 Sep 17.
Article in English | MEDLINE | ID: mdl-25093298

ABSTRACT

Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level provides a starting point for improved therapeutic intervention. SNPs in the innate immune receptor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syndrome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show that these polymorphisms cluster into two primary locations: the ATP/Mg(2+)-binding site and helical domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods.


Subject(s)
Cranial Nerve Diseases/genetics , Nod2 Signaling Adaptor Protein/genetics , Polymorphism, Single Nucleotide , Synovitis/genetics , Uveitis/genetics , Amino Acid Sequence , Amino Acid Substitution , Arthritis , Cranial Nerve Diseases/enzymology , Genetic Association Studies , Genetic Predisposition to Disease , HEK293 Cells , Humans , Hydrolysis , Models, Molecular , Molecular Sequence Data , NF-kappa B/metabolism , Nod1 Signaling Adaptor Protein/physiology , Nod2 Signaling Adaptor Protein/metabolism , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Transport , Sarcoidosis , Signal Transduction , Synovitis/enzymology , Uveitis/enzymology
5.
J Biol Chem ; 289(33): 22900-22914, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-24958724

ABSTRACT

Following activation, the cytoplasmic pattern recognition receptor nucleotide-binding oligomerization domain-containing protein 1 (NOD1) interacts with its adaptor protein receptor-interacting protein 2 (RIP2) to propagate immune signaling and initiate a proinflammatory immune response. This interaction is mediated by the caspase recruitment domain (CARD) of both proteins. Polymorphisms in immune proteins can affect receptor function and predispose individuals to specific autoinflammatory disorders. In this report, we show that mutations in helix 2 of the CARD of NOD1 disrupted receptor function but did not interfere with RIP2 interaction. In particular, N43S, a rare polymorphism, resulted in receptor dysfunction despite retaining normal cellular localization, protein folding, and an ability to interact with RIP2. Mutation of Asn-43 resulted in an increased tendency to form dimers, which we propose is the source of this dysfunction. We also demonstrate that mutation of Lys-443 and Tyr-474 in RIP2 disrupted the interaction with NOD1. Mapping the key residues involved in the interaction between NOD1 and RIP2 to the known structures of CARD complexes revealed the likely involvement of both type I and type III interfaces in the NOD1·RIP2 complex. Overall we demonstrate that the NOD1-RIP2 signaling axis is more complex than previously assumed, that simple engagement of RIP2 is insufficient to mediate signaling, and that the interaction between NOD1 and RIP2 constitutes multiple CARD-CARD interfaces.


Subject(s)
Nod1 Signaling Adaptor Protein/metabolism , Protein Multimerization/physiology , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Signal Transduction/physiology , HEK293 Cells , Humans , Mutation , Nod1 Signaling Adaptor Protein/genetics , Protein Structure, Secondary , Protein Structure, Tertiary , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics
6.
FEBS Lett ; 588(17): 2830-6, 2014 Aug 25.
Article in English | MEDLINE | ID: mdl-24960071

ABSTRACT

NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD-NACHT linker and one in the NACHT itself.


Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/metabolism , Nod2 Signaling Adaptor Protein/chemistry , Nod2 Signaling Adaptor Protein/metabolism , Animals , CARD Signaling Adaptor Proteins , Humans , Mice , Models, Molecular , Protein Binding , Protein Structure, Tertiary
7.
Front Immunol ; 4: 317, 2013.
Article in English | MEDLINE | ID: mdl-24109482

ABSTRACT

Amino acids with functional or key structural roles display higher degrees of conservation through evolution. The comparative analysis of protein sequences from multiple species and/or between homologous proteins can be highly informative in the identification of key structural and functional residues. Residues which in turn provide insight into the molecular mechanisms of protein function. We have explored the genomic and amino acid conservation of the prototypic innate immune genes NOD1 and NOD2. NOD1 orthologs were found in all vertebrate species analyzed, whilst NOD2 was absent from the genomes of avian, reptilian and amphibian species. Evolutionary trace analysis was used to identify highly conserved regions of NOD1 and NOD2 across multiple species. Consistent with the known functions of NOD1 and NOD2 highly conserved patches were identified that matched the Walker A and B motifs and provided interaction surfaces for the adaptor protein RIP2. Other patches of high conservation reflect key structural functions as predicted by homology models. In addition, the pattern of residue conservation within the leucine-rich repeat (LRR) region of NOD1 and NOD2 is indicative of a conserved mechanism of ligand recognition involving the concave surface of the LRRs.

9.
J Biol Chem ; 287(27): 23057-67, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-22549783

ABSTRACT

Nucleotide binding and oligomerization domain-containing protein 2 (NOD2/Card15) is an intracellular protein that is involved in the recognition of bacterial cell wall-derived muramyl dipeptide. Mutations in the gene encoding NOD2 are associated with inherited inflammatory disorders, including Crohn disease and Blau syndrome. NOD2 is a member of the nucleotide-binding domain and leucine-rich repeat-containing protein gene (NLR) family. Nucleotide binding is thought to play a critical role in signaling by NLR family members. However, the molecular mechanisms underlying signal transduction by these proteins remain largely unknown. Mutations in the nucleotide-binding domain of NOD2 have been shown to alter its signal transduction properties in response to muramyl dipeptide in cellular assays. Using purified recombinant protein, we now demonstrate that NOD2 binds and hydrolyzes ATP. Additionally, we have found that the purified recombinant protein is able to bind directly to muramyl dipeptide and can associate with known NOD2-interacting proteins in vitro. Binding of NOD2 to muramyl dipeptide and homo-oligomerization of NOD2 are enhanced by ATP binding, suggesting a model of the molecular mechanism for signal transduction that involves binding of nucleotide followed by binding of muramyl dipeptide and oligomerization of NOD2 into a signaling complex. These findings set the stage for further studies into the molecular mechanisms that underlie detection of muramyl dipeptide and assembly of NOD2-containing signaling complexes.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/metabolism , Adenosine Triphosphate/metabolism , Immunity, Innate/physiology , Nod2 Signaling Adaptor Protein/metabolism , Signal Transduction/immunology , Adenosine Triphosphatases/metabolism , Adenosine Triphosphate/analogs & derivatives , Animals , Bacterial Proteins/metabolism , Baculoviridae/genetics , Cells, Cultured , Chromatography, Affinity , HEK293 Cells , Humans , Insecta/cytology , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/immunology , Protein Binding/physiology , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/metabolism
10.
Proteins ; 80(8): 2063-70, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22513832

ABSTRACT

The innate immune response provides our first line of defence against infection. Over the course of evolution, pathogens have evolved numerous strategies to either avoid activating or to limit the effectiveness of the innate immune system. The Kaposi's sarcoma-associated herpesvirus (KSHV) contains tegument proteins in the virion that contribute to immune evasion and aid the establishment of viral infection. For example, the KSHV tegument protein ORF63 modulates inflammasome activation to inhibit the innate immune response against the virus. Understanding the likely structure of proteins involved in immune evasion enables potential mechanisms of action to be proposed. To understand more fully how ORF63 modulates the innate immune system we have utilized widely available bioinformatics tools to analyze the primary protein sequence of ORF63 and to predict its secondary and tertiary structure. We found that ORF63 is predicted to be almost entirely alpha-helical and may possess similarity to HEAT repeat containing proteins. Consequently, ORF63 is unlikely to be a viral homolog of the NLR protein family. ORF63 may inhibit the innate immune response by flexibly interacting with its target protein and inhibiting the recruitment of protein co-factors and/or conformational changes required for immune signaling.


Subject(s)
Herpesvirus 8, Human/chemistry , Protein Structure, Secondary , Protein Structure, Tertiary , Viral Proteins/chemistry , Amino Acid Sequence , Computational Biology/methods , Humans , Molecular Sequence Data , Receptors, Cytoplasmic and Nuclear/chemistry , Sarcoma, Kaposi/chemistry , Sarcoma, Kaposi/virology , Structural Homology, Protein
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