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Antiviral signaling through pattern recognition receptors 总被引:10,自引:0,他引:10
Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response. 相似文献
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Peptide mapping of conformational epitopes in a human malarial parasite heat shock protein 总被引:1,自引:0,他引:1
S J Richman T S Vedvick R T Reese 《Journal of immunology (Baltimore, Md. : 1950)》1989,143(1):285-292
A protein of 75 kDa is found in large quantities throughout the blood stages of the human malarial parasite, Plasmodium falciparum. Based on a partial amino acid sequence for p75, previously deduced from a cDNA clone encoding approximately 40% of the molecule, secondary structural predictions were made. The potential role of long range effects on the tertiary structure of the protein stabilized by disulfide bridges was determined by reduction and alkylation of the fusion protein. Five regions were then chosen for peptide modeling. Peptides of 16, 28, 49, 64, and 76 residues were synthesized and used to immunize rabbits. All but the 16-residue peptides were capable of stimulating boostable IgG antibody responses in rabbits, but the antibody produced against the 49 mer did not react with the native parasite protein. Thus, the 28, 64, and 76 residue peptides represent good immunologic models for portions of the P. falciparum 75-kDa protein capable of stimulating both T and B cells in rabbits. The peptides were also used to probe whether any of the selected regions contain epitopes which react with antibodies from owl monkeys immune to P. falciparum. Of these peptides, two were found to be consistently recognized in ELISA by four owl monkey antisera raised in response to malarial infection. Because these two peptides model a cysteine-containing region of the protein, owl monkey sera were also used as probes of the importance of disulfide bonding in maintaining the native structure. The results obtained were consistent with a folding pattern for p75 that incorporates a disulfide bond between cysteines 161 and 194. These results also suggest that most of the epitopes recognized in this part of p75 by the immune system of the monkey are created by folding of the molecule. 相似文献
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An increasing number of studies have implicated that the activation of innate immune system and inflammatory mechanisms are of importance in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms in response to pathogens or tissue injury, which is performed via germ-line encoded pattern-recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) or dangers-associated molecular patterns (DAMPs). Intracellular pathways linking immune and inflammatory response to ion channel expression and function have been recently identified. Among ion channels, transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes. In this review, we summarize current knowledge about classifications, functions, and interactions of TRP channels and PRRs, which may provide new insights into their roles in the pathogenesis of inflammatory diseases. 相似文献
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Lacking an adaptive immune system, plants largely rely on plasma membrane‐resident pattern recognition receptors (PRRs) to sense pathogen invasion. The activation of PRRs leads to the profound immune responses that coordinately contribute to the restriction of pathogen multiplication. Protein post‐translational modifications dynamically shape the intensity and duration of the signalling pathways. In this review, we discuss the specific regulation of PRR activation and signalling by protein ubiquitination, endocytosis and degradation, with a particular focus on the bacterial flagellin receptor FLS2 (flagellin sensing 2) in Arabidopsis. 相似文献
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FLS2 and EFR are pattern recognition receptors in Arabidopsis thaliana perceiving the bacterial proteins flagellin and Elongation factor Tu (EF-Tu). Both receptors belong to the >200 membered protein family of Leucine-Rich Repeat Receptor Kinases (LRR-RKs) in Arabidopsis. FLS2 and EFR are engaged in the activation of a common intracellular signal output and they belong to the same subfamily of LRR-RKs, sharing structural features like the intracellular kinase domain and the ectodomain organized in LRRs. On the amino acid sequence level, however, they are only <50% identical even in their kinase domains. In our recently published paper1 we demonstrated that it is possible to create chimeric receptors of EFR and FLS2 that are fully functional in ligand binding and receptor activation. Chimeric receptors consisting of the complete EFR ectodomain and the FLS2 kinase domain proved to be sensitive to elf18, the minimal peptide required for EF-Tu recognition, similar to the native EFR. In chimeric receptors where parts of the FLS2 ectodomain were swapped into the EFR LRR-domain, the receptor function was strongly affected even in cases with only small fragments exchanged. In this addendum we want to address problems and limits but also possibilities and chances of studying receptor functions using a chimeric approach.Key words: pattern recognition receptors, chimeric receptors, MAMP, flagellin perception, FLS2, EFRIn the Arabidopsis genome exist >600 genes that are predicted to encode for receptor-like kinases (RLKs).2,3 More than 200 of them have ectodomains with LRRs. Physiological functions have been attributed only to a rather small percentage of them. Examples for known receptor-ligand pairs in A. thaliana include the well studied BRI1/Brassionlide,4,5 AtPEPR1/Pep25,6 HAESA/IDA7 or CLV1/CLV3.8 While these LRR-RKs detect endogenous ligands, other members of this family function as immunoreceptors that detect ligands indicative of ‘non-self,’ such as pathogen associated molecular patterns (PAMPs). Examples of such LRR-RKs include FLS2 (Flagellin Sensing 2) and EFR (EF-Tu Receptor) from Arabidopsis and XA21 from rice.9–11 The corresponding ligands have been identified as the flg22-epitope of bacterial flagellin for FLS2, the N-terminus of bacterial EF-Tu represented by the elf18 peptide for EFR, and the sulfated Avr21 peptide from Xanthomonas for XA21, respectively. LRR-ectodomains with related function in pathogen recognition occur also in so-called receptor-like proteins that lack the cytoplasmic kinase domains. Well studied examples include several Cf-receptor proteins which confer resistance against the fungus Cladosporium fulvum (Cf) in a gene-for-gene dependent manner. Thereby, different Cf-proteins function as recognition systems with specificity for factors determined by corresponding AvrCf products of the fungal pathogen.12,13Receptor activation of the well studied receptor BRI1 by its ligand brassinolide involves interaction with a further receptor kinase, BAK1 (BRI1-associated receptor kinase 1).5,14 Most interestingly, BAK1, or one of the four BAK1-related receptor kinases of the SERK protein family, also acts as a co-receptor for the ligand-dependent activation of FLS2, AtPEPR1 and EFR.15–17 It seems that the co-receptor BAK1 plays an important role in activation of receptor kinases, serving different intracellular signaling pathways and output programs.18Up to now, little is known about the molecular details of ligand binding by the ectodomain in the apoplast and how this process leads to activation of the output signaling by the kinase moiety in the cytoplasm. The interaction with the co-receptor BAK1 suggests an activation process involving a ligand-induced intramolecular conformational change of the LRR-RK that then allows heterodimerization with the co-receptor BAK1. An initial task in elucidation of this activation process consists in defining the exact sites in the ectodomains of the receptors that interact with their corresponding ligands. So far, the clearest results for mapping ligand binding sites on LRR-receptor proteins were obtained with directed point mutations within the LRR domains as performed with the tomato receptor-like protein Cf-9,19,20 and the Arabidopsis FLS2. There, a series of directed point mutations helped to map the LRRs 9–15 as a subdomain essential for interaction with the ligand flg22.21 Another interesting and promising approach consists in swaps of receptor sub-domains or exchanges of LRRs. In a remarkable, pioneering experiment this approach was used to produce chimeric receptors with the ectodomain of the brassinosteroid receptor BRI1 from Arabidopsis and the kinase domain of the immunoreceptor XA21 from rice.22 This chimera was reported to recognize the “developmental signal” brassinolide but to trigger characteristic cellular defense responses. In a recent publication23 a domain swap between the ectodomain of the Wall Associated Kinase 1 (WAK1) and EFR was used to gain evidence for a function of the WAK1 ectodomain as a pectin receptor. Chimeric forms of the Cf receptor-like protein were used to identify subdomains carrying the specificity for the corresponding effectors from the C. fulvum pathogens.24 However, as a limitation of this analysis, for none of these tomato resistance proteins a direct interaction with the corresponding effector proteins of the pathogen could be demonstrated so far.25In our work, recently published in the Journal of Biochemistry,1 we used the Arabidopsis thaliana receptors FLS2 and EFR to generate receptor chimeras. The main goal was to study the elf18 binding site in the EFR LRR-domain. In initial attempts we used EFR-constructs lacking some of the LRRs to narrow down the interaction site on the ectodomain. However, all of these truncated ectodomain versions lacking the transmembrane domain or more turned out to be unable in binding elf18 and triggering responses. In a second approach, we used the replacement of receptor parts with fragments from the structurally related receptor AtFLS2. These chimeras were tested for proper expression, localization, functionality in several plant defence related assays and affinity for the ligand elf18 in binding assays. The chimera with the complete EFR ectodomain swapped to the Kinase of FLS2 was fully functional as EF-Tu receptor. Since both receptors are known to trigger the same set of defense responses this might be not unexpected. Nevertheless, it is noteworthy that the two receptors show ∼45% sequence identity in their kinase domain, a degree of identity also shared with the kinase domains of receptors involved in other output programs, like BRI1. The 21 LRRs of EFR are sufficient for specifying full affinity for the elf18 as a ligand (Receptor Ethylene response Oxidative burst FRK-promoter induction Binding affinitiy for elf18 EFR ≥0.01 nM ≥0.01 nM ≥0.001 nM IC50 ∼10 nM E-oJM/F ≥0.01 nM ≥0.01 nM ≥0.001 nM IC50 ∼10 nM E-21/F ≥10 nM ≥10 nM ≥0.1 nM IC50 ∼10 nM E-19/F no response no response no response no binding F-6/E no response ≥1,000 nM no response IC50 ∼100 nM