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1.
Proc Natl Acad Sci U S A ; 117(31): 18832-18839, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32709746

RESUMO

Plant and animal intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors detect pathogen-derived molecules and activate defense. Plant NLRs can be divided into several classes based upon their N-terminal signaling domains, including TIR (Toll-like, Interleukin-1 receptor, Resistance protein)- and CC (coiled-coil)-NLRs. Upon ligand detection, mammalian NAIP and NLRC4 NLRs oligomerize, forming an inflammasome that induces proximity of its N-terminal signaling domains. Recently, a plant CC-NLR was revealed to form an inflammasome-like hetero-oligomer. To further investigate plant NLR signaling mechanisms, we fused the N-terminal TIR domain of several plant NLRs to the N terminus of NLRC4. Inflammasome-dependent induced proximity of the TIR domain in planta initiated defense signaling. Thus, induced proximity of a plant TIR domain imposed by oligomerization of a mammalian inflammasome is sufficient to activate authentic plant defense. Ligand detection and inflammasome formation is maintained when the known components of the NLRC4 inflammasome is transferred across kingdoms, indicating that NLRC4 complex can robustly function without any additional mammalian proteins. Additionally, we found NADase activity of a plant TIR domain is necessary for plant defense activation, but NADase activity of a mammalian or a bacterial TIR is not sufficient to activate defense in plants.


Assuntos
Proteínas NLR , Imunidade Vegetal , Proteínas de Plantas , Proteínas Recombinantes de Fusão , Transdução de Sinais , Animais , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Mamíferos , Proteínas NLR/química , Proteínas NLR/genética , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Imunidade Vegetal/genética , Imunidade Vegetal/imunologia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Domínios Proteicos/genética , Domínios Proteicos/fisiologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
2.
Cell Mol Life Sci ; 77(20): 3963-3976, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32277261

RESUMO

The immune system of plants is highly complex. It involves pattern-triggered immunity (PTI), which is signaled and manifested through branched multi-step pathways. To counteract this, pathogen effectors target and inhibit individual PTI steps. This in turn can cause specific plant cytosolic nucleotide-binding leucine-rich repeat (NLR) receptors to activate effector-triggered immunity (ETI). Plants and pathogens have many genes encoding NLRs and effectors, respectively. Yet, only a few segregate genetically as resistance (R) genes and avirulence (Avr) effector genes in wild-type populations. In an attempt to explain this contradiction, a model is proposed where far most of the NLRs, the effectors and the effector targets keep one another in a silent state. In this so-called "iceberg model", a few NLR-effector combinations are genetically visible above the surface, while the vast majority is hidden below. Besides, addressing the existence of many NLRs and effectors, the model also helps to explain why individual downregulation of many effectors causes reduced virulence and why many lesion-mimic mutants are found. Finally, the iceberg model accommodates genuine plant susceptibility factors as potential effector targets.


Assuntos
Arabidopsis/imunologia , Imunidade Vegetal/imunologia , Animais , Humanos , Proteínas NLR/imunologia , Doenças das Plantas/imunologia , Proteínas de Plantas/imunologia
3.
PLoS Pathog ; 16(4): e1008475, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32339200

RESUMO

The nucleotide-binding, leucine-rich repeat-containing (NLR) class of immune receptors of plants and animals recognize pathogen-encoded proteins and trigger host defenses. Although animal NLRs form oligomers upon pathogen recognition to activate downstream signaling, the mechanisms of plant NLR activation remain largely elusive. Tm-22 is a plasma membrane (PM)-localized coiled coil (CC)-type NLR and confers resistance to Tobacco mosaic virus (TMV) by recognizing its viral movement protein (MP). In this study, we found that Tm-22 self-associates upon recognition of MP. The CC domain of Tm-22 is the signaling domain and its function requires PM localization and self-association. The nucleotide-binding (NB-ARC) domain is important for Tm-22 self-interaction and regulates activation of the CC domain through its nucleotide-binding and self-association. (d)ATP binding may alter the NB-ARC conformation to release its suppression of Tm-22 CC domain-mediated cell death. Our findings provide the first example of signaling domain for PM-localized NLR and insight into PM-localized NLR activation.


Assuntos
Proteínas NLR/metabolismo , Doenças das Plantas/imunologia , Proteínas de Plantas/metabolismo , Receptores Imunológicos/metabolismo , Tabaco/metabolismo , Tabaco/virologia , Membrana Celular/metabolismo , Resistência à Doença , Proteínas NLR/imunologia , Doenças das Plantas/virologia , Imunidade Vegetal , Proteínas de Plantas/imunologia , Ligação Proteica , Domínios Proteicos , Receptores Imunológicos/imunologia , Transdução de Sinais , Tabaco/imunologia , Vírus do Mosaico do Tabaco/metabolismo , Vírus do Mosaico do Tabaco/patogenicidade
4.
Int J Mol Sci ; 21(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019187

RESUMO

Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.


Assuntos
Retinopatia Diabética/imunologia , Glaucoma/imunologia , Inflamassomos/imunologia , Degeneração Macular/imunologia , Edema Macular/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteínas NLR/imunologia , Olho/imunologia , Humanos , Imunidade Inata
5.
Life Sci ; 248: 117456, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097666

RESUMO

AIMS: In this study, we will investigate the therapeutic effects of berberine (BBR) in Helicobacter pylori (H. pylori) induced chronic atrophic gastritis (CAG). Furthermore, potential mechanisms of BBR in regulating IRF8-IFN-γ signaling axis will also be investigated. MATERIALS AND METHODS: H. pylori were utilized to establish CAG model of rats. Therapeutic effects of BBR on serum supernatant indices, and histopathology of stomach were analyzed in vivo. Moreover, GES-1 cells were infected by H. pylori, and intervened with BBR in vitro. Cell viability, morphology, proliferation, and quantitative analysis were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression in IRF8-IFN-γ signaling axis were measured. KEY FINDINGS: Results showed serum supernatant indices including IL-17, CXCL1, and CXCL9 were downregulated by BBR intervention, while, G-17 increased significantly. Histological injuries of gastric mucosa induced by H. pylori also were alleviated. Moreover, cell viability and morphology changes of GES-1 cells were improved by BBR intervention. In addition, proinflammatory genes and IRF8-IFN-γ signaling axis related genes, including Ifit3, Upp1, USP18, Nlrc5, were suppressed by BBR administration in vitro and in vivo. The proteins expression related to IRF8-IFN-γ signaling axis, including Ifit3, IRF1 and Ifit1 were downregulated by BBR intervention.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Gastrite Atrófica/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Fatores Reguladores de Interferon/genética , Interferon gama/genética , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Quimiocina CXCL9/antagonistas & inibidores , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Doença Crônica , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Gastrite Atrófica/genética , Gastrite Atrófica/imunologia , Gastrite Atrófica/microbiologia , Regulação da Expressão Gênica , Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/crescimento & desenvolvimento , Helicobacter pylori/patogenicidade , Humanos , Fatores Reguladores de Interferon/antagonistas & inibidores , Fatores Reguladores de Interferon/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Interleucina-17/agonistas , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Proteínas NLR/antagonistas & inibidores , Proteínas NLR/genética , Proteínas NLR/imunologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Uridina Fosforilase/antagonistas & inibidores , Uridina Fosforilase/genética , Uridina Fosforilase/imunologia
6.
Nat Rev Immunol ; 20(2): 95-112, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31558839

RESUMO

The innate immune system has the capacity to detect 'non-self' molecules derived from pathogens, known as pathogen-associated molecular patterns, via pattern recognition receptors. In addition, an increasing number of endogenous host-derived molecules, termed damage-associated molecular patterns (DAMPs), have been found to be sensed by various innate immune receptors. The recognition of DAMPs, which are produced or released by damaged and dying cells, promotes sterile inflammation, which is important for tissue repair and regeneration, but can also lead to the development of numerous inflammatory diseases, such as metabolic disorders, neurodegenerative diseases, autoimmune diseases and cancer. Here we examine recent discoveries concerning the roles of DAMP-sensing receptors in sterile inflammation and in diseases resulting from dysregulated sterile inflammation, and then discuss insights into the cross-regulation of these receptors and their ligands.


Assuntos
Alarminas/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Humanos , Lectinas Tipo C/imunologia , Proteínas NLR/imunologia , Receptor para Produtos Finais de Glicação Avançada/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Tolerância a Antígenos Próprios/imunologia , Receptores Toll-Like/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia
7.
Adv Exp Med Biol ; 1172: 119-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628654

RESUMO

The nucleotide-binding domain (NBD) and leucine-rich repeat (LRR) containing (NLR) proteins are a large family of intracellular immune receptors conserved in both animals and plants. Mammalian NLRs function as pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) or host-derived danger associated molecular patterns (DAMPs). PAMP or DAMP perception activates NLRs which consequently recruit pro-caspase-1 directly or indirectly. These sequential events result in formation of large multimeric protein complexes termed inflammasomes that mediate caspase-1 activation for pyroptosis and cytokine secretion. Recent structural and biochemical studies provide significant insights into the acting mechanisms of NLR proteins. In this chapter, we review and discuss these studies concerning autoinhibition, ligand recognition, activation of NLRs, and assembly of NLR inflammasomes.


Assuntos
Inflamassomos , Proteínas NLR , Animais , Inflamassomos/biossíntese , Inflamassomos/imunologia , Proteínas NLR/química , Proteínas NLR/imunologia , Plantas , Receptores de Reconhecimento de Padrão
8.
Proc Natl Acad Sci U S A ; 116(37): 18479-18487, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451649

RESUMO

Tetep is a rice cultivar known for broad-spectrum resistance to blast, a devastating fungal disease. The molecular basis for its broad-spectrum resistance is still poorly understood. Is it because Tetep has many more NLR genes than other cultivars? Or does Tetep possess multiple major NLR genes that can individually confer broad-spectrum resistance to blast? Moreover, are there many interacting NLR pairs in the Tetep genome? We sequenced its genome, obtained a high-quality assembly, and annotated 455 nucleotide-binding site leucine-rich repeat (NLR) genes. We cloned and tested 219 NLR genes as transgenes in 2 susceptible cultivars using 5 to 12 diversified pathogen strains; in many cases, fewer than 12 strains were successfully cultured for testing. Ninety cloned NLRs showed resistance to 1 or more pathogen strains and each strain was recognized by multiple NLRs. However, few NLRs showed resistance to >6 strains, so multiple NLRs are apparently required for Tetep's broad-spectrum resistance to blast. This was further supported by the pedigree analyses, which suggested a correlation between resistance and the number of Tetep-derived NLRs. In developing a method to identify NLR pairs each of which functions as a unit, we found that >20% of the NLRs in the Tetep and 3 other rice genomes are paired. Finally, we designed an extensive set of molecular markers for rapidly introducing clustered and paired NLRs in the Tetep genome for breeding new resistant cultivars. This study increased our understanding of the genetic basis of broad-spectrum blast resistance in rice.


Assuntos
Resistência à Doença/genética , Magnaporthe/imunologia , Proteínas NLR/genética , Oryza/genética , Doenças das Plantas/imunologia , Proteínas de Plantas/genética , Sistemas CRISPR-Cas/genética , Mapeamento Cromossômico , Clonagem Molecular , Técnicas de Inativação de Genes , Redes Reguladoras de Genes/imunologia , Genoma de Planta/genética , Proteínas NLR/imunologia , Oryza/imunologia , Oryza/microbiologia , Filogenia , Melhoramento Vegetal , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/imunologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/imunologia , Plantas Geneticamente Modificadas/microbiologia , Análise de Sequência de DNA
9.
J Biol Chem ; 294(35): 13006-13016, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31296569

RESUMO

Unconventional integrated domains in plant intracellular immune receptors of the nucleotide-binding leucine-rich repeat (NLRs) type can directly bind translocated effector proteins from pathogens and thereby initiate an immune response. The rice (Oryza sativa) immune receptor pairs Pik-1/Pik-2 and RGA5/RGA4 both use integrated heavy metal-associated (HMA) domains to bind the effectors AVR-Pik and AVR-Pia, respectively, from the rice blast fungal pathogen Magnaporthe oryzae These effectors both belong to the MAX effector family and share a core structural fold, despite being divergent in sequence. How integrated domains in NLRs maintain specificity of effector recognition, even of structurally similar effectors, has implications for understanding plant immune receptor evolution and function. Here, using plant cell death and pathogenicity assays and protein-protein interaction analyses, we show that the rice NLR pair Pikp-1/Pikp-2 triggers an immune response leading to partial disease resistance toward the "mis-matched" effector AVR-Pia in planta and that the Pikp-HMA domain binds AVR-Pia in vitro We observed that the HMA domain from another Pik-1 allele, Pikm, cannot bind AVR-Pia, and it does not trigger a plant response. The crystal structure of Pikp-HMA bound to AVR-Pia at 1.9 Å resolution revealed a binding interface different from those formed with AVR-Pik effectors, suggesting plasticity in integrated domain-effector interactions. The results of our work indicate that a single NLR immune receptor can bait multiple pathogen effectors via an integrated domain, insights that may enable engineering plant immune receptors with extended disease resistance profiles.


Assuntos
Magnaporthe/imunologia , Proteínas NLR/imunologia , Oryza/imunologia , Doenças das Plantas/imunologia , Modelos Moleculares , Proteínas NLR/química , Oryza/microbiologia , Doenças das Plantas/microbiologia , Ligação Proteica
10.
Nat Commun ; 10(1): 3252, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324801

RESUMO

Nucleotide-binding leucine-rich repeat (NLR) immune receptors play a critical role in defence against pathogens in plants and animals. However, we know very little about NLR-interacting proteins and the mechanisms that regulate NLR levels. Here, we used proximity labeling (PL) to identify the proteome proximal to N, which is an NLR that confers resistance to Tobacco mosaic virus (TMV). Evaluation of different PL methods indicated that TurboID-based PL provides more efficient levels of biotinylation than BioID and BioID2 in plants. TurboID-based PL of N followed by quantitative proteomic analysis and genetic screening revealed multiple regulators of N-mediated immunity. Interestingly, a putative E3 ubiquitin ligase, UBR7, directly interacts with the TIR domain of N. UBR7 downregulation leads to an increased amount of N protein and enhanced TMV resistance. TMV-p50 effector disrupts the N-UBR7 interaction and relieves negative regulation of N. These findings demonstrate the utility of TurboID-based PL in plants and the N-interacting proteins we identified enhance our understanding of the mechanisms underlying NLR regulation.


Assuntos
Proteínas NLR/imunologia , Proteínas de Plantas/imunologia , Receptores Imunológicos/imunologia , Coloração e Rotulagem/métodos , Tabaco/imunologia , Ubiquitina-Proteína Ligases/imunologia , Proteínas NLR/metabolismo , Imunidade Vegetal/imunologia , Proteínas de Plantas/metabolismo , Ligação Proteica , Proteoma/imunologia , Proteoma/metabolismo , Receptores Imunológicos/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/imunologia , Tabaco/metabolismo , Tabaco/virologia , Vírus do Mosaico do Tabaco/imunologia , Vírus do Mosaico do Tabaco/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
11.
Integr Comp Biol ; 59(4): 819-829, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31236558

RESUMO

Historically mechanisms with which basal animals such as reef-building corals use to respond to changing and increasingly stressful environments have remained elusive. However, the increasing availability of genomic and transcriptomic data from these organisms has provided fundamental insights into the biology of these critically important ecosystem engineers. Notably, insights into cnidarians gained in the post-genomics age have revealed a surprisingly complex immune system which bears a surprising level of similarity with the vertebrate innate immune system. This system has been critically linked to how corals respond to the two most prominent threats on a global scale, emerging coral diseases and increasing water temperature, which are recognized cellularly as either foreign or domestic threats, respectively. These threats can arise from pathogenic microbes or internal cellular dysfunction, underscoring the need to further understand mechanisms corals use to sense and respond to threats to their cellular integrity. In this investigation and meta-analysis, we utilize resources only recently available in the post-genomic era to identify and characterize members of an underexplored class of molecules known as NOD-like receptors in the endangered Caribbean coral Orbicella faveolata. We then leverage these data to identify pathways possibly mediated by NLRs in both O. faveolata and the ecologically important branching coral Acropora digitifera. Overall, we find support that this class of proteins may provide a mechanistic link to how reef-building corals respond to threats both foreign and domestic.


Assuntos
Antozoários/genética , Antozoários/imunologia , Imunidade Inata/genética , Proteínas NLR/imunologia , Animais , Espécies em Perigo de Extinção , Evolução Molecular , Imunidade Inata/imunologia , Proteínas NLR/genética , Estresse Fisiológico
12.
Int Rev Immunol ; 38(4): 131-156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066339

RESUMO

The innate immune system-based recognition of the pathogens or their PAMPs initiates the pro-inflammatory immune response required for the maintenance of the homeostasis. The dysregulation of this innate immune response causes several diseases including sepsis, cancer and autoimmunity. However, pattern recognition receptors (PRRs) including toll-like receptors (TLRs), complement receptors (CRs) and NLRs of inflammasomes regulate both these processes of recognition of pathogens/PAMPs and their clearance. These three major components of the innate immune arm were studied independently/separately for a long time. Various studies have now shown that they work in close association and their crosstalk is required for the pathogen clearance via regulating the process of phagocytosis and mounting the controlled but potent immune response. The loss or inhibition of any of the three components affects the other in a positive/negative manner that can affect the immune process required for efficient host defense. The present review is designed to provide the current information on their evolution like the requirement of TLRs and inflammasomes for pathogen recognition even in the presence of complements system and their interaction during various immunological processes including phagocytosis, autophagy and inflammatory immune response.


Assuntos
Proteínas do Sistema Complemento/imunologia , Imunidade Inata/imunologia , Inflamassomos/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Animais , Humanos , Proteínas NLR/imunologia , Padrões Moleculares Associados a Patógenos/imunologia , Fagocitose
13.
Nat Commun ; 10(1): 2292, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123263

RESUMO

The wheat Pm3 resistance gene against the powdery mildew pathogen occurs as an allelic series encoding functionally different immune receptors which induce resistance upon recognition of isolate-specific avirulence (AVR) effectors from the pathogen. Here, we describe the identification of five effector proteins from the mildew pathogens of wheat, rye, and the wild grass Dactylis glomerata, specifically recognized by the PM3B, PM3C and PM3D receptors. Together with the earlier identified AVRPM3A2/F2, the recognized AVRs of PM3B/C, (AVRPM3B2/C2), and PM3D (AVRPM3D3) belong to a large group of proteins with low sequence homology but predicted structural similarities. AvrPm3b2/c2 and AvrPm3d3 are conserved in all tested isolates of wheat and rye mildew, and non-host infection assays demonstrate that Pm3b, Pm3c, and Pm3d are also restricting the growth of rye mildew on wheat. Furthermore, divergent AVR homologues from non-adapted rye and Dactylis mildews are recognized by PM3B, PM3C, or PM3D, demonstrating their involvement in host specificity.


Assuntos
Ascomicetos/fisiologia , Proteínas Fúngicas/imunologia , Especificidade de Hospedeiro , Doenças das Plantas/imunologia , Proteínas de Plantas/imunologia , Triticum/imunologia , Ascomicetos/isolamento & purificação , Ascomicetos/patogenicidade , Dactylis/microbiologia , Resistência à Doença/imunologia , Grão Comestível/imunologia , Grão Comestível/microbiologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genoma Fúngico , Estudo de Associação Genômica Ampla , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Doenças das Plantas/microbiologia , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Secale/microbiologia , Tabaco/genética , Tabaco/microbiologia , Triticum/microbiologia
14.
Fish Shellfish Immunol ; 91: 172-179, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103555

RESUMO

The inflammatory response of fish to LPS is subdued, attributed to absence of TLR4, a key pro-inflammatory receptor for LPS in mammals. Nevertheless, LPS is processed in fish in a T-independent manner and is a protective antigen in fish vaccines, yet pathways for processing LPS in fish remain to be elucidated. Here, we report that caspases and NOD-like receptor inflammasomes typically responsible for LPS recognition and processing in mammals lack critical domains or are absent in barramundi (Lates calcarifer). On the other hand, leucocyte integrins MAC-1 and LFA-1 were detected on the surface of neutrophil- and lymphocyte-like cells respectively in the barramundi spleen by immunocytochemistry, and leucocytes displaying MAC-1 or LFA-1 bound to Factor X and ESM-1 respectively. Exposure to MAC-1 and LFA-1 induced significant IL-1ß expression post-stimulation with LPS compared to unstimulated and isotype controls, but the differences observed in TNF-α expression were inconclusive. Our findings implicate MAC-1 and LFA-1 involvement in immune processing of LPS in barramundi and in antigen processing in fish.


Assuntos
Imunidade Inata/genética , Inflamassomos/imunologia , Leucócitos/imunologia , Lipopolissacarídeos/farmacologia , Perciformes/imunologia , Animais , Caspases/imunologia , Integrinas/imunologia , Proteínas NLR/imunologia , Filogenia
15.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995767

RESUMO

To ward off pathogens and pests, plants use a sophisticated immune system. They use pattern-recognition receptors (PRRs), as well as nucleotide-binding and leucine-rich repeat (NB-LRR) domains, for detecting nonindigenous molecular signatures from pathogens. Plant PRRs induce local and systemic immunity. Plasma-membrane-localized PRRs are the main components of multiprotein complexes having additional transmembrane and cytosolic kinases. Topical research involving proteins and their interactive partners, along with transcriptional and posttranscriptional regulation, has extended our understanding of R-gene-mediated plant immunity. The unique LRR domain conformation helps in the best utilization of a surface area and essentially mediates protein-protein interactions. Genome-wide analyses of inter- and intraspecies PRRs and NB-LRRs offer innovative information about their working and evolution. We reviewed plant immune responses with relevance to PRRs and NB-LRRs. This article focuses on the significant functional diversity, pathogen-recognition mechanisms, and subcellular compartmentalization of plant PRRs and NB-LRRs. We highlight the potential biotechnological application of PRRs and NB-LRRs to enhance broad-spectrum disease resistance in crops.


Assuntos
Proteínas NLR/imunologia , Doenças das Plantas/imunologia , Imunidade Vegetal , Proteínas de Plantas/imunologia , Plantas/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Produtos Agrícolas/imunologia , Imunidade Inata
16.
Biosci Rep ; 39(4)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30837326

RESUMO

Innate immunity comprises several inflammation-related modulatory pathways which receive signals from an array of membrane-bound and cytoplasmic pattern recognition receptors (PRRs). The NLRs (NACHT (NAIP (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein) and Leucine-Rich Repeat (LRR) domain containing proteins) relate to a large family of cytosolic innate receptors, involved in detection of intracellular pathogens and endogenous byproducts of tissue injury. These receptors may recognize pathogen-associated molecular patterns (PAMPs) and/or danger-associated molecular patterns (DAMPs), activating host responses against pathogen infection and cellular stress. NLR-driven downstream signals trigger a number of signaling circuitries, which may either initiate the formation of inflammasomes and/or activate nuclear factor κB (NF-κB), stress kinases, interferon response factors (IRFs), inflammatory caspases and autophagy. Disruption of those signals may lead to a number of pro-inflammatory conditions, eventually promoting the onset of human malignancies. In this review, we describe the structures and functions of the most well-defined NLR proteins and highlight their association and biological impact on a diverse number of cancers.


Assuntos
Imunidade Inata , Proteínas NLR/imunologia , Neoplasias/imunologia , Animais , Humanos , Inflamassomos/imunologia , Inflamação/imunologia , NF-kappa B/imunologia , Neoplasias/patologia , Padrões Moleculares Associados a Patógenos/imunologia , Receptores de Reconhecimento de Padrão/imunologia
17.
Biochem Biophys Res Commun ; 511(2): 468-475, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30797557

RESUMO

Increasing evidence indicates that the NOD-like receptors (NLRs) family may act as critical back-up defenses and provide synergistic responses when confronted with persistent danger. However, the precise regulatory mechanism of NLRs and the contribution of NLRs to cancer are still unknown. In our previous study, we found that estrogen receptors (ERs) have a close connection with NLRs in the inflammatory response. Here, ERs are first identified as NLRs transcription regulation factors, both regulate NLRs expression and promote inflammasome co-localization. Furthermore, we identified that NLRP3 was differentially expressed in colon normal and cancer cells, selective ERα antagonist could significantly decrease pro-inflammatory cytokines expression, suppress proliferation and promote apoptosis by inhibited NLRP3 expression and inflammasome activity. In short, the research demonstrates that ERs participate in the NLR-associated signaling pathway in cancer by directly regulating NLRs. Our results provide novel insight into ERs as therapeutic targets in NLR-related inflammation and cancer.


Assuntos
Carcinogênese/imunologia , Inflamassomos/imunologia , Proteínas NLR/imunologia , Receptores Estrogênicos/imunologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Humanos , Inflamassomos/análise , Inflamação/imunologia , Inflamação/patologia , Modelos Moleculares , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteínas NLR/análise , Receptores Estrogênicos/análise , Transdução de Sinais
18.
Mol Immunol ; 113: 6-10, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29198621

RESUMO

A critical role of pattern recognition receptors (PRRs) is to influence adaptive immune responses by regulating antigen presentation. Engagement of PRRs in dendritic cells (DCs) increases MHC class I antigen presentation and CD8+ T-cell activation by cross-presented peptides but the molecular mechanisms underlying these effects are not completely understood. Studies looking at the role of PRRs in cross-presentation have been largely limited to TLRs but the role of other PRRs such as cytosolic nucleotide-binding oligomerization domain-like (NOD-like) receptors remains particularly enigmatic. Here we discuss recent evidence of the role of PRRs on cross-presentation and consider how cytosolic NLR-associated pathways, such as NOD2, may integrate these signals resulting in effective adaptive CD8+ T cells responses.


Assuntos
Apresentação Cruzada/imunologia , Imunidade Inata/imunologia , Proteínas NLR/imunologia , Animais , Linfócitos T CD8-Positivos , Humanos , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais/imunologia
19.
PLoS Biol ; 16(12): e2005821, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30540748

RESUMO

The ability to induce a defense response after pathogen attack is a critical feature of the immune system of any organism. Nucleotide-binding leucine-rich repeat receptors (NLRs) are key players in this process and perceive the occurrence of nonself-activities or foreign molecules. In plants, coevolution with a variety of pests and pathogens has resulted in repertoires of several hundred diverse NLRs in single individuals and many more in populations as a whole. However, the mechanism by which defense signaling is triggered by these NLRs in plants is poorly understood. Here, we show that upon pathogen perception, NLRs use their N-terminal domains to transactivate other receptors. Their N-terminal domains homo- and heterodimerize, suggesting that plant NLRs oligomerize upon activation, similar to the vertebrate NLRs; however, consistent with their large number in plants, the complexes are highly heterometric. Also, in contrast to metazoan NLRs, the N-terminus, rather than their centrally located nucleotide-binding (NB) domain, can mediate initial partner selection. The highly redundant network of NLR interactions in plants is proposed to provide resilience to perturbation by pathogens.


Assuntos
Proteínas NLR/genética , Proteínas NLR/imunologia , Proteínas de Plantas/genética , Genoma de Planta/genética , Genoma de Planta/imunologia , Imunidade Inata , Alface/genética , Doenças das Plantas/imunologia , Imunidade Vegetal/genética , Imunidade Vegetal/imunologia , Plantas/genética , Plantas/imunologia , Domínios Proteicos/genética , Análise de Sequência de Proteína , Transdução de Sinais
20.
Elife ; 72018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30460894

RESUMO

Rotaviruses (RVs), a leading cause of severe diarrhea in young children and many mammalian species, have evolved multiple strategies to counteract the host innate immunity, specifically interferon (IFN) signaling through RV non-structural protein 1 (NSP1). However, whether RV structural components also subvert antiviral response remains under-studied. Here, we found that MAVS, critical for the host RNA sensing pathway upstream of IFN induction, is degraded by the RV RNA methyl- and guanylyl-transferase (VP3) in a host-range-restricted manner. Mechanistically, VP3 localizes to the mitochondria and mediates the phosphorylation of a previously unidentified SPLTSS motif within the MAVS proline-rich region, leading to its proteasomal degradation and blockade of IFN-λ production in RV-infected intestinal epithelial cells. Importantly, VP3 inhibition of MAVS activity contributes to enhanced RV replication and to viral pathogenesis in vivo. Collectively, our findings establish RV VP3 as a viral antagonist of MAVS function in mammals and uncover a novel pathogen-mediated inhibitory mechanism of MAVS signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Capsídeo/genética , Interações Hospedeiro-Patógeno , Interferons/genética , Infecções por Rotavirus/genética , Rotavirus/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Células COS , Proteínas do Capsídeo/imunologia , Caspase 1/genética , Caspase 1/imunologia , Chlorocebus aethiops , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Células HEK293 , Células HT29 , Humanos , Íleo/imunologia , Íleo/virologia , Interferons/imunologia , Camundongos , Células NIH 3T3 , Proteínas NLR/genética , Proteínas NLR/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Rotavirus/crescimento & desenvolvimento , Rotavirus/imunologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Transdução de Sinais
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