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At least 19 recordsLinked to original sources
PubMed2006

Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf.

Legionella pneumophila is an intracellular bacterium that causes an acute form of pneumonia called Legionnaires' disease. After infection of human macrophages, the Legionella-containing phagosome (LCP) avoids fusion with the lysosome allowing intracellular replication of the bacterium. In macrophages derived from most mouse strains, the LCP is delivered to the lysosome resulting in Legionella degradation and restricted bacterial growth. Mouse macrophages lacking the NLR protein Ipaf or its downstream effector caspase-1 are permissive to intracellular Legionella replication. However, the mechanism by which Ipaf restricts Legionella replication is not well understood. Here we demonstrate that the presence of flagellin and a competent type IV secretion system are critical for Legionella to activate caspase-1 in macrophages. Activation of caspase-1 in response to Legionella infection also required host Ipaf, but not TLR5. In the absence of Ipaf or caspase-1 activation, the LCP acquired endoplasmic reticulum-derived vesicles, avoided fusion with the lysosome, and allowed Legionella replication. Accordingly a Legionella mutant lacking flagellin did not activate caspase-1, avoided degradation, and replicated in wild-type macrophages. The regulation of phagosome maturation by Ipaf occurred within 2 h after infection and was independent of macrophage cell death. In vivo studies confirmed that flagellin and Ipaf play an important role in the control of Legionella clearance. These results reveal that Ipaf restricts Legionella replication through the regulation of phagosome maturation, providing a novel function for NLR proteins in host defense against an intracellular bacterium.

Adaptor Proteins, Signal Transducing↗
PubMed2025

In silico prediction method for plant Nucleotide-binding leucine-rich repeat- and pathogen effector interactions.

Plant Nucleotide-binding leucine-rich repeat (NLR) proteins play a crucial role in effector recognition and activation of Effector triggered immunity following pathogen infection. Genome sequencing advancements have led to the identification of a myriad of NLRs in numerous agriculturally important plant species. However, deciphering which NLRs recognize specific pathogen effectors remains challenging. Predicting NLR-effector interactions in silico will provide a more targeted approach for experimental validation, critical for elucidating function, and advancing our understanding of NLR-triggered immunity. In this study, NLR-effector protein complex structures were predicted using AlphaFold2-Multimer for all experimentally validated NLR-effector interactions reported in literature. Binding affinities- and energies were predicted using 97 machine learning models from Area-Affinity. We show that AlphaFold2-Multimer predicted structures have acceptable accuracy and can be used to investigate NLR-effector interactions in silico. Binding affinities for 58 NLR-effector complexes ranged between -8.5 and -10.6 log(K), and binding energies between -11.8 and -14.4 kcal/mol-1, depending on the Area-Affinity model used. For 2427 "forced" NLR-effector complexes, these estimates showed larger variability, enabling identification of novel NLR-effector interactions with 99% accuracy using an Ensemble machine learning model. The narrow range of binding energies- and affinities for "true" interactions suggest a specific change in Gibbs free energy, and thus conformational change, is required for NLR activation. This is the first study to provide a method for predicting NLR-effector interactions, applicable to all pathosystems. Finally, the NLR-Effector Interaction Classification (NEIC) resource can streamline research efforts by identifying NLRs important for plant-pathogen resistance, advancing our understanding of plant immunity.

Plant Proteins↗
PubMed2000

Oxygen detoxification in the strict anaerobic archaeon Archaeoglobus fulgidus: superoxide scavenging by neelaredoxin.

Archaeoglobus fulgidus is a hyperthermophilic sulphate-reducing archaeon. It has an optimum growth temperature of 83 degrees C and is described as a strict anaerobe. Its genome lacks any homologue of canonical superoxide (O2.-) dismutases. In this work, we show that neelaredoxin (Nlr) is the main O2.- scavenger in A. fulgidus, by studying both the wild-type and recombinant proteins. Nlr is a 125-amino-acid blue-coloured protein containing a single iron atom/molecule, which in the oxidized state is high spin ferric. This iron centre has a reduction potential of +230 mV at pH 7.0. Nitroblue tetrazolium-stained gel assays of cell-soluble extracts show that Nlr is the main protein from A. fulgidus which is reactive towards O2.-. Furthermore, it is shown that Nlr is able to both reduce and dismutate O2.-, thus having a bifunctional reactivity towards O2.-. Kinetic and spectroscopic studies indicate that Nlr's superoxide reductase activity may allow the cell to eliminate O2.- quickly in a NAD(P)H-dependent pathway. On the other hand, Nlr's superoxide dismutation activity will allow the cell to detoxify O2.- independently of the cell redox status. Its superoxide dismutase activity was estimated to be 59 U mg-1 by the xanthine/xanthine oxidase assay at 25 degrees C. Pulse radiolysis studies with the isolated and reduced Nlr proved unambiguously that it has superoxide dismutase activity; at pH 7.1 and 83 degrees C, the rate constant is 5 x 106 M-1 s-1. Besides the superoxide dismutase activity, soluble cell extracts of A. fulgidus also exhibit catalase and NAD(P)H/oxygen oxidoreductase activities. By putting these findings together with the entire genomic data available, a possible oxygen detoxification mechanism in A. fulgidus is discussed.

Amino Acid Sequence↗
PubMed2005

The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals.

The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) proteins and are emerging as important immune regulators in animals. CLR proteins contain NBD-LRR motifs and are linked to a limited number of distinct N-terminal domains including transactivation, CARD (caspase activation and recruitment), and pyrin domains (PyD). The CLR gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, and its expression in these cells is reduced by Toll-like receptor (TLR) agonists tumor necrosis factor (TNF) alpha and Mycobacterium tuberculosis. Monarch-1 reduces NFkappaB activation by TLR-signaling molecules MyD88, IRAK-1 (type I interleukin-1 receptor-associated protein kinase), and TRAF6 (TNF receptor (TNFR)-associated factor) as well as TNFR signaling molecules TRAF2 and RIP1 but not the downstream NFkappaB subunit p65. This indicates that Monarch-1 is a negative regulator of both TLR and TNFR pathways. Reducing Monarch-1 expression with small interference RNA in myeloid/monocytic cells caused a dramatic increase in NFkappaB activation and cytokine expression in response to TLR2/TLR4 agonists, TNFalpha, or M. tuberculosis infection, suggesting that Monarch-1 is a negative regulator of inflammation. Because Monarch-1 is the first CLR protein that interferes with both TLR2 and TLR4 activation, the mechanism of this interference is significant. We find that Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation. Mutants containing the NBD-LRR or PyD-NBD also blocked IRAK-1 activation. This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Naip5/Birc1e and susceptibility to Legionella pneumophila.

Genetic analysis in mice is a powerful approach for the identification of genes and proteins that have a key role at the interface of the host-pathogen interaction. The Lgn1 locus has been found to control the intracellular replication of Legionella pneumophila in murine macrophages. Using functional complementation in transgenic mice, the Naip5/Birc1e gene has been identified as responsible for the Lgn1 effect. The classification of Naip5/Birc1e as a member of the NLR protein family suggests that Naip5/Birc1e acts as an intracellular sensor of L. pneumophila. The nature of the signal transduced by Naip5/Birc1e in response to Legionella products is of great interest but is currently unknown. Here, several possible scenarios are presented.

Animals↗
PubMed2006

Crystal structure of the Nod1 caspase activation and recruitment domain.

Nod-like receptors (NLRs), Nod1 and Nod2 are cytosolic detectors of pathogen-associated molecular patterns (PAMPs). Nod1 is a three-domain protein, consisting of a caspase activation and recruitment domain (CARD), a nucleotide-binding oligomerization domain (NOD), and a leucine-rich repeat domain (LRR). The binding of PAMPs to the LRR results in the activation of signaling through homophilic CARD-CARD interactions. Several CARD structures have been determined, including a recent NMR structure of Nod1 CARD. In contrast to the reported NMR structure, the crystal structure reported here is a dimer, where the sixth helix is swapped between two monomers. While the overall structure is very similar to the known CARD structures, this is the first report of a homodimeric CARD structure. The ability of the CARD to exist in monomeric and dimeric forms suggests another level of regulation in the activation of NLR proteins.

Binding Sites↗
PubMed2005

NACHT-LRR proteins (NLRs) in bacterial infection and immunity.

Eukaryotes have evolved systems to detect bacterial intrusion. Recognition of bacteria relies on the sensing of pathogen associated molecular patterns (PAMPs) by host pattern recognition molecules (PRMs), which include various families of leucine-rich repeat (LRR) bearing proteins in plants and animals. Detection of microbes often occurs outside the cell. Recent findings now indicate that mammals have also evolved strategies to recognize bacteria inside the cell via members of the NACHT-LRR protein family (NLRs). Here, we review the biology of these mammalian NLRs and the emerging view of their important, role not solely as PRMs but as signalling platforms and regulators of immunity.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation.

The innate immune system is the most ancestral and ubiquitous system of defence against microbial infection. The microbial sensing proteins involved in innate immunity recognize conserved and often structural components of microorganisms. One class of these pattern-recognition molecules, the Toll-like receptors (TLRs), are involved in detection of microbes in the extracellular compartment whereas a newly discovered family of proteins, the NBS-LRR proteins (for nucleotide-binding site and leucine-rich repeat), are involved in intracellular recognition of microbes and their products. NBS-LRR proteins are characterized by three structural domains: a C-terminal leucine-rich repeat (LRR) domain able to sense a microbial motif, an intermediary nucleotide binding site (NBS) essential for the oligomerization of the molecule that is necessary for the signal transduction induced by different N-terminal effector motifs, such as a pyrin domain (PYD), a caspase-activating and recruitment domain (CARD) or a baculovirus inhibitor of apoptosis protein repeat (BIR) domain. Two of these family members, Nod1 and Nod2, play a role in the regulation of pro-inflammatory pathways through NF-kappaB induced by bacterial ligands. Recently, it was shown that Nod2 recognizes a specific peptidoglycan motif from bacteria, muramyl dipeptide (MDP). A surprising number of human genetic disorders have been linked to NBS-LRR proteins. For example, mutations in Nod2, which render the molecule insensitive to MDP and unable to induce NF-kappaB activation when stimulated, are associated with susceptibility to a chronic intestinal inflammatory disorder, Crohn's disease. Conversely, mutations in the NBS region of Nod2 induce a constitutive activation of NF-kappaB and are responsible for Blau syndrome, another auto-inflammatory disease. Nalp3, which is an NBS-LRR protein with an N-terminal Pyrin domain, is also implicated in rare auto-inflammatory disorders. In conclusion, NBS-LRR molecules appear as a new family of intracellular receptors of innate immunity able to detect specific bacterial compounds and induce inflammatory response; the dysregulation of these processes due to mutations in the genes encoding these proteins is involved in numerous auto-inflammatory disorders.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Cloning of a novel putative G-protein-coupled receptor (NLR) which is expressed in neuronal and lymphatic tissue.

A novel G-protein-coupled receptor was isolated from mouse and rat neuronal and lymphatic tissues. The amino acid sequence of the rat receptor (rNLR) shows an overall homology of 80% to a recently cloned receptor from Burkitt's lymphoma cells (BLR1) which is exclusively expressed in lymphatic tissues [(1992) Eur. J. Immunol. 22, 2795]. Much less homology between rNLR and BLR1 was observed at the N-terminus (about 40%), whereas rNLR and the mouse homologue mNLR show 92% amino acid identity. Northern blot analysis of NLR revealed a predominant 5.5 kb mRNA species in various brain regions and neuronal cell lines, whereas in the spleen a 3 kb transcript is predominant. This distribution suggests a role of NLR in the nervous and immune systems.

Amino Acid Sequence↗
PubMed2006

The impact of endogenous triggers on trauma-associated inflammation.

PURPOSE OF REVIEW: Inflammation immediately starting after trauma is a consequence of an efficient host defense system that is not only capable of sensing exogenous and pathogen-derived danger signals, but also endogenous, multifunctional alarm signals, which both can initiate an inflammatory response. RECENT FINDINGS: Even in the absence of infection, Toll-like receptors play an important role in inflammation via recognition of host-derived, endogenous 'damage signals' like heat shock proteins and 'alarmins' such as the nuclear protein high-mobility group box protein 1, which are presented as a result of tissue trauma. In addition to the Toll-like receptors, a number of other receptors are involved in the host inflammatory response, including the new family of nucleotide oligomerization domain-like receptors capable of sensing the presence of danger signals in the cytoplasm. Important links occur between the Toll-like receptors as key inducers of the pro-forms of interleukin-1beta and interleukin-18 and the activation of certain nucleotide oligomerization domain-like receptors, resulting in inflammasome formation--an essential process leading to the secretion of these proinflammatory cytokines. SUMMARY: In addition to improved insights into the regulation of traumatic inflammation and the etiology of the systemic inflammatory response syndrome, some endogenous immune triggers seem to have the potential to serve as novel biomarkers in predicting post-traumatic complications.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.

The estrogen-responsive B box protein (EBBP) and Pyrin belong to a family of structurally related proteins. While mutations in the pyrin gene cause an autoinflammatory disease, the biological function of EBBP is unknown. In this study, we identified the proinflammatory cytokine interleukin-1beta (IL-1beta) as an EBBP-binding partner. Furthermore, caspase-1 and NACHT, LRR and Pyrin domain containing protein (NALP) 1, two components of the recently identified inflammasome, a platform for the activation of caspase-1, also interact with EBBP. These proteins bind to the RFP domain of EBBP, suggesting that this domain of so far unknown function is an important protein-binding domain. EBBP was secreted in a caspase-1-dependent manner from cultured cells, and its secretion was enhanced by IL-1beta. Vice versa, endogenous and overerexpressed EBBP increased IL-1beta secretion. These results provide evidence for a role of EBBP in innate immunity by enhancing the alternative secretion pathway of IL-1beta.

Adaptor Proteins, Signal Transducing↗
PubMed2006

[Periodic fever syndromes].

Periodic fever syndromes comprise a group of disorders characterized by attacks of seemingly unprovoked inflammation. The genetic causes of five hereditary autoinflammatory syndromes have been identified in the last few years: familial Mediterranean fever, the cryopyrinopathies [Muckle-Wells, chronic infantile neurological, cutaneous, articular syndrome (CINCA) and familial autoinflammatory syndromes], TNF-receptor associated periodic syndrome, cyclic neutropenia syndrome and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. The study of periodic fever syndromes has progressed from clinical characterization to genetic analysis and to the definition of the functional defects linking genes or domains to apoptotic proteins and signal transduction pathways. This new research opens the way for more specific treatment options with a further improvement in prognosis and outcome.

Adolescent↗
PubMed2026

APOM-associated inflammation and apoptosis in stroke-exacerbated myocardial infarction: implications for brain-heart interactions.

Brain-heart syndrome (BHS) describes cardiac dysfunction secondary to central nervous system injury, with acute ischemic stroke (AIS) serving as a critical driver that exacerbates myocardial infarction (MI). This study aimed to elucidate the role of Apolipoprotein M (APOM) in stroke-aggravated MI and to explore its underlying systemic and molecular mechanisms. Clinical data were analyzed to evaluate the correlation between stroke and MI. A combined mouse model of middle cerebral artery occlusion (MCAO) and MI was established to assess neurological and cardiac injury. Quantitative proteomics and Weighted Gene Co-expression Network Analysis (WGCNA) were employed to screen key differentially expressed proteins. The role of APOM in myocardial injury was validated using APOM-knockout (KO) mice. Furthermore, nuclear-cytoplasmic fractionation, immunofluorescence, and Western blot were performed to investigate its effects on the Saa1 and NF-κB signaling, NLRP3-related inflammatory signaling pathway, and lipid metabolism pathways. Clinical analysis indicated that stroke is a significant risk factor for MI (OR = 4.5). In the mouse model, MCAO significantly exacerbated post-MI electrocardiographic abnormalities, myocardial inflammatory response, while elevating circulating levels of cTnT and IL-1β. Proteomics identified a significant downregulation of APOM in the heart, brain, and serum post-stroke, a trend consistent with observations in AIS patients. Further experiments revealed that APOM deficiency markedly worsened cardiac conduction disturbances, histological damage, and inflammatory responses in MI mice. Mechanistically, the loss of APOM upregulates the acute-phase protein Saa1, triggers NF-κB phosphorylation and nuclear translocation, and enhances inflammatory signaling related to inflammasomes, while simultaneously mediating cytokine release from cardiomyocytes. Concurrently, APOM deficiency led to a significant decrease in sphingosine-1-phosphate (S1P) and also caused myocardial lipid droplet accumulation and metabolite changes. Additionally, the loss of APOM increased the expression of D-dimer and fibrinogen family proteins. Our findings suggest that APOM is a potential cardioprotective agent post-AIS. Downregulation of APOM may exacerbate myocardial injury after MI by elevating Saa1 expression, activating the NF-κB pathway and the inflammasome-mediated signaling, and inducing lipid metabolic disorders and coagulation-associated alterations. APOM may represent a potential therapeutic target for the intervention of brain-heart syndrome.

Animals↗
PubMed2006

Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene.

UNLABELLED: We report on a patient with chronic infantile neurological cutaneous and articular (CINCA) syndrome. Sequence analysis revealed a novel missense mutation in exon 4 of the CIAS1 gene. The patient was unresponsive to several treatments including prednisolone, immunosuppressants (azathioprine and cyclosporin), disease-modifying antirheumatic drugs (DMARDs: penicillamine, salazopyrin and methotrexate) and the tumour necrosis factor-alpha (TNF-a)-blocker infliximab. At 32 mo of age, administration of the recombinant human interleukin-1 receptor antagonist anakinra commenced, which caused an immediate and marked improvement in the clinical symptoms and laboratory test results. Continuous inhibition of the inflammation required a dose of 1.0 mg/kg every 12 h. CONCLUSION: Following the diagnosis of CINCA syndrome, anakinra treatment should be commenced as the first line of therapy.

Antirheumatic Agents↗
PubMed2003

NMR structure of the apoptosis- and inflammation-related NALP1 pyrin domain.

Signaling in apoptosis and inflammation is often mediated by proteins of the death domain superfamily in the Fas/FADD/Caspase-8 or the Apaf-1/Caspase-9 pathways. This superfamily currently comprises the death domain (DD), death effector domain (DED), caspase recruitment domain (CARD), and pyrin domain (PYD) subfamilies. The PYD subfamily is most abundant, but three-dimensional structures are only available for the subfamilies DD, DED, and CARD, which have an antiparallel arrangement of six alpha helices as common fold. This paper presents the NMR structure of PYD of NALP1, a protein that is involved in the innate immune response and is a component of the inflammasome. The structure of NALP1 PYD differs from all other known death domain superfamily structures in that the third alpha helix is replaced by a flexibly disordered loop. This unique feature appears to relate to the molecular basis of familial Mediterranean fever (FMF), a genetic disease caused by single-point mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins.

We report the deduced amino acid sequences of two alternately spliced isoforms, designated DEFCAP-L and -S, that differ in 44 amino acids and encode a novel member of the mammalian Ced-4 family of apoptosis proteins. Similar to the other mammalian Ced-4 proteins (Apaf-1 and Nod1), DEFCAP contains a caspase recruitment domain (CARD) and a putative nucleotide binding domain, signified by a consensus Walker's A box (P-loop) and B box (Mg(2+)-binding site). Like Nod1, but different from Apaf-1, DEFCAP contains a putative regulatory domain containing multiple leucine-rich repeats (LRR). However, a distinguishing feature of the primary sequence of DEFCAP is that DEFCAP contains at its NH(2) terminus a pyrin-like motif and a proline-rich sequence, possibly involved in protein-protein interactions with Src homology domain 3-containing proteins. By using in vitro coimmunoprecipitation experiments, both long and short isoforms were capable of strongly interacting with caspase-2 and exhibited a weaker interaction with caspase-9. Transient overexpression of full-length DEFCAP-L, but not DEFCAP-S, in breast adenocarcinoma cells MCF7 resulted in significant levels of apoptosis. In vitro death assays with transient overexpression of deletion constructs of both isoforms using beta-galactosidase as a reporter gene in MCF7 cells suggest the following: 1) the nucleotide binding domain may act as a negative regulator of the killing activity of DEFCAP; 2) the LRR/CARD represents a putative constitutively active inducer of apoptosis; 3) the killing activity of LRR/CARD is inhibitable by benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone and to a lesser extent by Asp-Glu-Val-Asp (OMe)-fluoromethyl ketone; and 4) the CARD is critical for killing activity of DEFCAP. These results suggest that DEFCAP is a novel member of the mammalian Ced-4 family of proteins capable of inducing apoptosis, and understanding its regulation may elucidate the complex nature of the mammalian apoptosis-promoting machinery.

Adaptor Proteins, Signal Transducing↗