RESUMEN
Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain mediate recognition of strain-specific pathogen effectors, typically via their C-terminal ligand-sensing domains1. Effector binding enables TIR-encoded enzymatic activities that are required for TIR-NLR (TNL)-mediated immunity2,3. Many truncated TNL proteins lack effector-sensing domains but retain similar enzymatic and immune activities4,5. The mechanism underlying the activation of these TIR domain proteins remain unclear. Here we show that binding of the TIR substrates NAD+ and ATP induces phase separation of TIR domain proteins in vitro. A similar condensation occurs with a TIR domain protein expressed via its native promoter in response to pathogen inoculation in planta. The formation of TIR condensates is mediated by conserved self-association interfaces and a predicted intrinsically disordered loop region of TIRs. Mutations that disrupt TIR condensates impair the cell death activity of TIR domain proteins. Our data reveal phase separation as a mechanism for the activation of TIR domain proteins and provide insight into substrate-induced autonomous activation of TIR signalling to confer plant immunity.
Asunto(s)
Adenosina Trifosfato , Arabidopsis , NAD , Nicotiana , Separación de Fases , Proteínas de Plantas , Dominios Proteicos , Adenosina Trifosfato/metabolismo , Arabidopsis/genética , Arabidopsis/inmunología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/inmunología , Proteínas de Arabidopsis/metabolismo , Muerte Celular , Mutación , NAD/metabolismo , Nicotiana/genética , Nicotiana/inmunología , Nicotiana/metabolismo , Proteínas NLR/química , Proteínas NLR/genética , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Enfermedades de las Plantas/inmunología , Inmunidad de la Planta/genética , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/inmunología , Proteínas de Plantas/metabolismo , Regiones Promotoras Genéticas , Dominios Proteicos/genética , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal , Receptores Toll-Like/química , Receptores de Interleucina-1/químicaRESUMEN
The inflammasome pathway is a critical early response mechanism of the host that detects pathogens, initiates the production of inflammatory cytokines, and recruits effector cells to the infection site. Nonetheless, the mechanism of inflammasome activation in coronavirus infection and its biological functions in host defense remain unclear. Transmissible gastroenteritis virus (TGEV), a member of the genus Alphacoronavirus, is a significant pathogen that mainly infects piglets and causes intestinal inflammation and inflammatory cell infiltration. Here, we investigated the mechanism of inflammasome activation in intestinal epithelial cells (IECs) infected with TGEV. We observed a substantial increase in interleukin 1ß (IL-1ß) and IL-18 levels in both IECs and TGEV-infected porcine intestinal tissues. Furthermore, TGEV infection resulted in increased activation of caspase-1 and the NLRP1 (NOD-like receptor [NLR]-containing pyrin domain [PYD]) inflammasome. Our findings revealed that TGEV infection impeded the interaction between porcine NLRP1 (pNLRP1) and porcine dipeptidyl peptidases 9 (pDPP9), yet it did not reduce the expression of pDPP9. Importantly, the ZU5 domain, not the function-to-find domain (FIIND) reported in human NLRP1, was identified as the minimal domain of pNLRP1 for pDPP9 binding. In addition, the robust type I IFN expression induced by TGEV infection also upregulated pNLRP1 expression and pNLRP1 itself acts as an interferon-stimulated gene to counteract TGEV infection. Our data demonstrate that pNLRP1 has antiviral capabilities against coronavirus infection, which highlights its potential as a novel therapeutic target for coronavirus antiviral therapy. IMPORTANCE Coronavirus primarily targets the epithelial cells of the respiratory and gastrointestinal tracts, leading to damage in both humans and animals. NLRP1 is a direct sensor for RNA virus infection which is highly expressed in epithelial barrier tissues. However, until recently, the precise molecular mechanisms underlying its activation in coronavirus infection and subsequent downstream events remained unclear. In this study, we demonstrate that the alphacoronavirus TGEV induces the production of IL-1ß and IL-18 and upregulates the expression of pNLRP1. Furthermore, we found that pNLRP1 can serve as an interferon-stimulated gene (ISG) to inhibit the infection of enterovirus TGEV. Our research highlights the crucial role of NLRP1 as a regulator of innate immunity in TGEV infection and shows that it may serve as a potential therapeutic target for the treatment of coronavirus infection.
Asunto(s)
Gastroenteritis Porcina Transmisible , Inflamasomas , Proteínas NLR , Virus de la Gastroenteritis Transmisible , Animales , Inflamasomas/inmunología , Interferón Tipo I , Interleucina-18 , Proteínas NLR/inmunología , Porcinos , Gastroenteritis Porcina Transmisible/inmunología , Gastroenteritis Porcina Transmisible/transmisiónRESUMEN
Plant cells possess a two-layered immune system consisting of pattern-triggered immunity (PTI) and effector-triggered immunity (ETI), mediated by cell surface pattern-recognition receptors and intracellular nucleotide-binding leucine-rich repeat receptors (NLRs), respectively. The CONSTITUTIVE EXPRESSION OF PR GENES 5 (CPR5) nuclear pore complex protein negatively regulates ETI, including ETI-associated hypersensitive response. Here, we show that CPR5 is essential for the activation of various PTI responses in Arabidopsis, such as resistance to the non-adapted bacterium Pseudomonas syringae pv. tomato DC3000 hrcC- . In a forward-genetic screen for suppressors of cpr5, we identified the mediator protein MED4. Mutation of MED4 in cpr5 greatly restored the defective PTI of cpr5. Our findings reveal that CPR5 plays opposite roles in regulating PTI and ETI, and genetically regulates PTI via MED4.
Asunto(s)
Proteínas de Arabidopsis , Proteínas de la Membrana , Inmunidad de la Planta , Arabidopsis/inmunología , Proteínas de Arabidopsis/inmunología , Proteínas de la Membrana/inmunología , Pseudomonas syringae/patogenicidad , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Receptores de Reconocimiento de Patrones/inmunología , Proteínas NLR/inmunologíaRESUMEN
Plant intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) detect pathogen effectors to trigger immune responses1. Indirect recognition of a pathogen effector by the dicotyledonous Arabidopsis thaliana coiled-coil domain containing NLR (CNL) ZAR1 induces the formation of a large hetero-oligomeric protein complex, termed the ZAR1 resistosome, which functions as a calcium channel required for ZAR1-mediated immunity2-4. Whether the resistosome and channel activities are conserved among plant CNLs remains unknown. Here we report the cryo-electron microscopy structure of the wheat CNL Sr355 in complex with the effector AvrSr356 of the wheat stem rust pathogen. Direct effector binding to the leucine-rich repeats of Sr35 results in the formation of a pentameric Sr35-AvrSr35 complex, which we term the Sr35 resistosome. Wheat Sr35 and Arabidopsis ZAR1 resistosomes bear striking structural similarities, including an arginine cluster in the leucine-rich repeats domain not previously recognized as conserved, which co-occurs and forms intramolecular interactions with the 'EDVID' motif in the coiled-coil domain. Electrophysiological measurements show that the Sr35 resistosome exhibits non-selective cation channel activity. These structural insights allowed us to generate new variants of closely related wheat and barley orphan NLRs that recognize AvrSr35. Our data support the evolutionary conservation of CNL resistosomes in plants and demonstrate proof of principle for structure-based engineering of NLRs for crop improvement.
Asunto(s)
Canales de Calcio , Microscopía por Crioelectrón , Proteínas NLR , Proteínas de Plantas , Receptores Inmunológicos , Triticum , Arabidopsis/inmunología , Arabidopsis/metabolismo , Arginina , Canales de Calcio/química , Canales de Calcio/inmunología , Canales de Calcio/metabolismo , Cationes/metabolismo , Leucina , Proteínas NLR/química , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Inmunidad de la Planta , Proteínas de Plantas/química , Proteínas de Plantas/inmunología , Proteínas de Plantas/metabolismo , Receptores Inmunológicos/química , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Triticum/inmunología , Triticum/metabolismo , Secuencias de Aminoácidos , Secuencia Conservada , ElectrofisiologíaRESUMEN
Throughout their evolution, plant nucleotide-binding leucine-rich-repeat receptors (NLRs) have acquired widely divergent unconventional integrated domains that enhance their ability to detect pathogen effectors. However, the functional dynamics that drive the evolution of NLRs with integrated domains (NLR-IDs) remain poorly understood. Here, we reconstructed the evolutionary history of an NLR locus prone to unconventional domain integration and experimentally tested hypotheses about the evolution of NLR-IDs. We show that the rice (Oryza sativa) NLR Pias recognizes the effector AVR-Pias of the blast fungal pathogen Magnaporthe oryzae. Pias consists of a functionally specialized NLR pair, the helper Pias-1 and the sensor Pias-2, that is allelic to the previously characterized Pia pair of NLRs: the helper RGA4 and the sensor RGA5. Remarkably, Pias-2 carries a C-terminal DUF761 domain at a similar position to the heavy metal-associated (HMA) domain of RGA5. Phylogenomic analysis showed that Pias-2/RGA5 sensor NLRs have undergone recurrent genomic recombination within the genus Oryza, resulting in up to six sequence-divergent domain integrations. Allelic NLRs with divergent functions have been maintained transspecies in different Oryza lineages to detect sequence-divergent pathogen effectors. By contrast, Pias-1 has retained its NLR helper activity throughout evolution and is capable of functioning together with the divergent sensor-NLR RGA5 to respond to AVR-Pia. These results suggest that opposite selective forces have driven the evolution of paired NLRs: highly dynamic domain integration events maintained by balancing selection for sensor NLRs, in sharp contrast to purifying selection and functional conservation of immune signaling for helper NLRs.
Asunto(s)
Evolución Molecular , Magnaporthe , Proteínas NLR , Oryza , Enfermedades de las Plantas , Proteínas de Plantas , Receptores Inmunológicos , Ligamiento Genético , Interacciones Huésped-Patógeno/inmunología , Magnaporthe/genética , Magnaporthe/patogenicidad , Proteínas NLR/genética , Proteínas NLR/inmunología , Oryza/inmunología , Oryza/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/genética , Proteínas de Plantas/inmunología , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunologíaRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.
Asunto(s)
COVID-19/inmunología , Inmunidad Innata , SARS-CoV-2/inmunología , Animales , COVID-19/metabolismo , COVID-19/virología , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Evasión Inmune , Inflamasomas/inmunología , Inflamasomas/metabolismo , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , SARS-CoV-2/patogenicidad , Transducción de Señal , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Internalización del VirusRESUMEN
Many members of the nucleotide-binding and oligomerization domain (NACHT)- and leucine-rich-repeat-containing protein (NLR) family play crucial roles in pathogen recognition and innate immune response regulation. In our previous work, a unique and Vibrio splendidus-inducible NLRC4 receptor comprising Ig and NACHT domains was identified from the sea cucumber Apostichopus japonicus, and this receptor lacked the CARD and LRR domains that are typical of common cytoplasmic NLRs. To better understand the functional role of AjNLRC4, we confirmed that AjNLRC4 was a bona fide membrane PRR with two transmembrane structures. AjNLRC4 was able to directly bind microbes and polysaccharides via its extracellular Ig domain and agglutinate a variety of microbes in a Ca2+-dependent manner. Knockdown of AjNLRC4 by RNA interference and blockade of AjNLRC4 by antibodies in coelomocytes both could significantly inhibit the phagocytic activity and elimination of V. splendidus. Conversely, overexpression of AjNLRC4 enhanced the phagocytic activity of V. splendidus, and this effect could be specifically blocked by treatment with the actin-mediated endocytosis inhibitor cytochalasin D but not other endocytosis inhibitors. Moreover, AjNLRC4-mediated phagocytic activity was dependent on the interaction between the intracellular domain of AjNLRC4 and the ß-actin protein and further regulated the Arp2/3 complex to mediate the rearrangement of the cytoskeleton and the polymerization of F-actin. V. splendidus was found to be colocalized with lysosomes in coelomocytes, and the bacterial quantities were increased after injection of chloroquine, a lysosome inhibitor. Collectively, these results suggested that AjNLRC4 served as a novel membrane PRR in mediating coelomocyte phagocytosis and further clearing intracellular Vibrio through the AjNLRC4-ß-actin-Arp2/3 complex-lysosome pathway.
Asunto(s)
Interacciones Huésped-Patógeno/inmunología , Proteínas NLR/inmunología , Fagocitosis/fisiología , Stichopus/microbiología , Vibriosis/inmunología , Actinas/metabolismo , Animales , Citoesqueleto/metabolismo , Proteínas NLR/metabolismo , Polimerizacion , Stichopus/metabolismo , Vibrio/inmunologíaRESUMEN
The innate immune system plays a pivotal role in the first line of host defense against infections and is equipped with patterns recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Several classes of PRRS, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) recognize distinct microbial components and directly activate immune cells. TLRs are transmembrane receptors, while NLRs and RLRs are intracellular molecules. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. The innate immune system also influences pathways involved in cancer immunosurveillance. Natural and synthetic agonists of TLRs, NLRs, or RLRs can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment, and are being explored as promising adjuvants in cancer immunotherapies. In this review, we provide a concise overview of TLRs, NLRs, and RLRs: their structure, functions, signaling pathways, and regulation. We also describe various ligands for these receptors and their possible application in treatment of hematopoietic diseases.
Asunto(s)
Proteína 58 DEAD Box/inmunología , Proteínas NLR/inmunología , Receptores Toll-Like/inmunología , Animales , Proteína 58 DEAD Box/metabolismo , Humanos , Inmunidad Innata/inmunología , Inmunidad Innata/fisiología , Factores Inmunológicos , Inmunoterapia , Ligandos , Proteínas NLR/metabolismo , Transporte de Proteínas , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal/inmunología , Receptores Toll-Like/metabolismoRESUMEN
Cooperation between receptors from the nucleotide-binding, leucine-rich repeats (NLR) superfamily is important for intracellular activation of immune responses. NLRs can function in pairs that, upon pathogen recognition, trigger hypersensitive cell death and stop pathogen invasion. Natural selection drives specialization of host immune receptors towards an optimal response, whilst keeping a tight regulation of immunity in the absence of pathogens. However, the molecular basis of co-adaptation and specialization between paired NLRs remains largely unknown. Here, we describe functional specialization in alleles of the rice NLR pair Pik that confers resistance to strains of the blast fungus Magnaporthe oryzae harbouring AVR-Pik effectors. We revealed that matching pairs of allelic Pik NLRs mount effective immune responses, whereas mismatched pairs lead to autoimmune phenotypes, a hallmark of hybrid necrosis in both natural and domesticated plant populations. We further showed that allelic specialization is largely underpinned by a single amino acid polymorphism that determines preferential association between matching pairs of Pik NLRs. These results provide a framework for how functionally linked immune receptors undergo co-adaptation to provide an effective and regulated immune response against pathogens. Understanding the molecular constraints that shape paired NLR evolution has implications beyond plant immunity given that hybrid necrosis can drive reproductive isolation.
Asunto(s)
Ascomicetos/fisiología , Proteínas NLR/genética , Oryza/genética , Enfermedades de las Plantas/inmunología , Proteínas de Plantas/genética , Receptores Inmunológicos , Alelos , Interacciones Huésped-Patógeno/inmunología , Proteínas NLR/inmunología , Oryza/inmunología , Enfermedades de las Plantas/microbiología , Inmunidad de la Planta/genética , Proteínas de Plantas/inmunología , Receptores Inmunológicos/metabolismoRESUMEN
Cell death is an essential immunological apparatus of host defense, but dysregulation of mutually inclusive cell deaths poses severe threats during microbial and parasitic infections leading to deleterious consequences in the pathological progression of infectious diseases. Nucleotide-binding oligomerization domain (NOD)-Leucine-rich repeats (LRR)-containing receptors (NLRs), also called nucleotide-binding oligomerization (NOD)-like receptors (NLRs), are major cytosolic pattern recognition receptors (PRRs), their involvement in the orchestration of innate immunity and host defense against bacteria, viruses, fungi and parasites, often results in the cleavage of gasdermin and the release of IL-1ß and IL-18, should be tightly regulated. NLRs are functionally diverse and tissue-specific PRRs expressed by both immune and non-immune cells. Beyond the inflammasome activation, NLRs are also involved in NF-κB and MAPK activation signaling, the regulation of type I IFN (IFN-I) production and the inflammatory cell death during microbial infections. Recent advancements of NLRs biology revealed its possible interplay with pyroptotic cell death and inflammatory mediators, such as caspase 1, caspase 11, IFN-I and GSDMD. This review provides the most updated information that caspase 8 skews the NLRP3 inflammasome activation in PANoptosis during pathogen infection. We also update multidimensional roles of NLRP12 in regulating innate immunity in a content-dependent manner: novel interference of NLRP12 on TLRs and NOD derived-signaling cascade, and the recently unveiled regulatory property of NLRP12 in production of type I IFN. Future prospects of exploring NLRs in controlling cell death during parasitic and microbial infection were highlighted.
Asunto(s)
Infecciones/inmunología , Proteínas NLR/fisiología , Enfermedades Parasitarias/inmunología , Animales , Muerte Celular/inmunología , Interacciones Microbiota-Huesped , Interacciones Huésped-Parásitos , Humanos , Mediadores de Inflamación/metabolismo , Proteínas NLR/genética , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal , Virus/inmunologíaRESUMEN
BACKGROUND: Abnormalities of inflammation have been implicated in the pathophysiology of depression and suicide, based on observations of increased levels of proinflammatory cytokines in the serum of people who were depressed and died by suicide. More recently, abnormalities in cytokines and innate immunity receptors such as toll-like receptors have also been observed in the postmortem brains of people who were depressed and died by suicide. In addition to toll-like receptors, another subfamily of innate immunity receptors known as NOD-like receptors containing pyrin (NLRPs) are the most widely present NOD-like receptors in the central nervous system. NLRPs also form inflammasomes that play an important role in brain function. We studied the role of NLRPs in depression and suicide. METHODS: We determined the protein and mRNA expression of NLRP1, NLRP3 and NLRP6 and the components of their inflammasomes (i.e., adaptor molecule apoptosis-associated speck-like protein [ASC], caspase1, caspase3, interleukin [IL]-1ß and IL-18) postmortem in the prefrontal cortex of people who were depressed and died by suicide, and in healthy controls. We determined mRNA levels using quantitative polymerase chain reaction, and we determined protein expression using Western blot immunolabelling. RESULTS: We found that the protein and mRNA expression levels of NLRP1, NLRP3, NLRP6, caspase3 and ASC were significantly increased in people who were depressed and died by suicide compared to healthy controls. LIMITATIONS: Some people who were depressed and died by suicide were taking antidepressant medication at the time of their death. CONCLUSION: Similar to toll-like receptors, NLRP and its inflammasomes were upregulated in people who were depressed and died by suicide compared to healthy controls. Innate immunity receptors in general - and NLRPs and inflammasomes in particular - may play an important role in the pathophysiology of depression and suicide.
Asunto(s)
Depresión/inmunología , Inmunidad Innata , Inflamasomas , Proteínas NLR/inmunología , Pirina , Suicidio Completo , Adulto , Autopsia , Encéfalo/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Inflamasomas/metabolismo , Masculino , ARN Mensajero , Receptores Toll-Like/metabolismoRESUMEN
Nucleotide-binding site and leucine-rich repeat receptors (NLRs) play pivotal roles in plant immunity. The regulation of NLR stability is essential to ensure effective immunity, whereas the exact mechanism is largely unclear. The Arabidopsis CC-NBS-LRR protein L5 (At1g12290) can induce cell death in Nicotiana benthamiana, but not in Arabidopsis thaliana. We screened the interactors of L5 by yeast two-hybrid, and found that the BOI can interact with the CC domain of L5. Transiently expressed BOI reduced the protein level of L5, and suppressed the auoactivity of L5 in N. benthamiana. BOI can interact and ubiquitinate L5 in vitro, and mediate the proteasomal degradation of L5 in N. benthamiana and Arabidopsis. The Lys425 in the NBS domain of L5 is the critical unbiquitin site for the degradation. In conclusion, our results reveal a mechanism for the control of the stability of L5 protein and for the suppressed of L5-triggered cell death by a RING-type E3 ligase through the ubiquitin proteasome system.
Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas NLR/metabolismo , Nicotiana/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Arabidopsis/inmunología , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/inmunología , Proteínas NLR/genética , Proteínas NLR/inmunología , Inmunidad de la Planta , Complejo de la Endopetidasa Proteasomal/inmunología , Dominios Proteicos , Nicotiana/inmunología , Ubiquitina-Proteína Ligasas/inmunologíaRESUMEN
Oxidative stress is a major contributor to the pathogenesis of various inflammatory diseases. Accumulating evidence has shown that oxidative stress is characterized by the overproduction of reactive oxygen species (ROS). Previous reviews have highlighted inflammatory signaling pathways, biomarkers, molecular targets, and pathogenetic functions mediated by oxidative stress in various diseases. The inflammatory signaling cascades are initiated through the recognition of host cell-derived damage associated molecular patterns (DAMPs) and microorganism-derived pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). In this review, the effects of PRRs from the Toll-like (TLRs), the retinoic acid-induced gene I (RIG-I)-like receptors (RLRs) and the NOD-like (NLRs) families, and the activation of these signaling pathways in regulating the production of ROS and/or oxidative stress are summarized. Furthermore, important directions for future studies, especially for pathogen-induced signaling pathways through oxidative stress are also reviewed. The present review will highlight potential therapeutic strategies relevant to inflammatory diseases based on the correlations between ROS regulation and PRRs-mediated signaling pathways.
Asunto(s)
Inflamación/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo , Alarminas/genética , Alarminas/inmunología , Alarminas/metabolismo , Animales , Autofagia , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/inmunología , Proteína 58 DEAD Box/metabolismo , Interacciones Microbiota-Huesped , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Inflamación/genética , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/terapia , Modelos Biológicos , Proteínas NLR/genética , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/terapia , Estrés Oxidativo , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Activación TranscripcionalRESUMEN
Plants rely on multiple immune systems to protect themselves from pathogens. When pattern-triggered immunity (PTI)-the first layer of the immune response-is no longer effective as a result of pathogenic effectors, effector-triggered immunity (ETI) often provides resistance. In ETI, host plants directly or indirectly perceive pathogen effectors via resistance proteins and launch a more robust and rapid defense response. Resistance proteins are typically found in the form of nucleotide-binding and leucine-rich-repeat-containing receptors (NLRs). Upon effector recognition, an NLR undergoes structural change and associates with other NLRs. The dimerization or oligomerization of NLRs signals to downstream components, activates "helper" NLRs, and culminates in the ETI response. Originally, PTI was thought to contribute little to ETI. However, most recent studies revealed crosstalk and cooperation between ETI and PTI. Here, we summarize recent advancements in our understanding of the ETI response and its components, as well as how these components cooperate in the innate immune signaling pathways. Based on up-to-date accumulated knowledge, this review provides our current perspective of potential engineering strategies for crop protection.
Asunto(s)
Inmunidad de la Planta , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Evolución Molecular , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , Modelos Inmunológicos , Proteínas NLR/genética , Proteínas NLR/inmunología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Inmunidad de la Planta/genética , Proteínas de Plantas/genética , Proteínas de Plantas/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
The innate immune system plays an important role in host defense against pathogenic infections. In the innate immune system, several families of innate pattern recognition receptors, including Toll-like receptors, RIG-I-like receptors, NOD-like receptors (NLRs), and DNA receptors (cytosolic sensors for DNA), are known to play vital roles in detecting and responding to various pathogens. In this study, we identified 29 NLRs in turbot including 4 NLRs from subfamily A: NOD1, NOD2, CIITA, NLRC5, 1 NLR from subfamily B: NLRB1, 21 NLRs from subfamily C: NLR-C3.1â¼NLRC3.21, 1 from NLRX subfamily, and two that do not fall within these subfamilies: APAF1, NWD1. Phylogenetic analysis showed that these NLR genes were clearly divided into five subfamilies. Protein-protein interaction network analysis showed that some of these NLR genes shared same interacting genes and might participate in signal transductions associated with immunity. The evolutionary pressure selection analysis showed that the Ka/Ks ratios for all detected NLR genes were much less than one, implying more synonymous changes than non-synonymous changes. In addition, tissue expression analysis showed that the relative higher expression levels were observed in gill, skin and intestine. Meanwhile, NLR genes expression after bacterial infection results showed that most NLR genes participated in the process of defense of V. anguillarum and A. salmonicida infections in mucosal tissues. Taken together, identification and expression profiling analysis of NLR genes can provide valuable information for further functional characterization of these genes in turbot.
Asunto(s)
Peces Planos/inmunología , Inmunidad Innata/fisiología , Inmunidad Mucosa/fisiología , Proteínas NLR/genética , Proteínas NLR/inmunología , Animales , Infecciones Bacterianas/inmunología , Enfermedades de los Peces/inmunología , Proteínas de Peces/inmunología , Peces Planos/genética , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Membrana Mucosa/inmunología , Filogenia , Mapas de Interacción de Proteínas , TranscriptomaRESUMEN
BACKGROUND: Toxoplasma gondii is a parasite that primarily infects through the oral route. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play crucial roles in the immune responses generated during parasitic infection and also drive the inflammatory response against invading parasites. However, little is known about the regulation of NLRs and inflammasome activation in T. gondii-infected human small intestinal epithelial (FHs 74 Int) cells. METHODS: FHs 74 Int cells infected with T. gondii were subsequently evaluated for morphological changes, cytotoxicity, expression profiles of NLRs, inflammasome components, caspase-cleaved interleukins (ILs), and the mechanisms of NLRP3 and NLRP6 inflammasome activation. Immunocytochemistry, lactate dehydrogenase assay, reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative RT-PCR, and western blotting techniques were utilized for analysis. RESULTS: Under normal and T. gondii-infected conditions, members of the NLRs, inflammasome components and caspase-cleaved ILs were expressed in the FHs Int 74 cells, except for NLRC3, NLRP5, and NLRP9. Among the NLRs, mRNA expression of NOD2, NLRP3, NLRP6, and NAIP1 was significantly increased in T. gondii-infected cells, whereas that of NLRP2, NLRP7, and CIITA mRNAs decreased significantly in a time-dependent manner. In addition, T. gondii infection induced NLRP3, NLRP6 and NLRC4 inflammasome activation and production of IL-1ß, IL-18, and IL-33 in FHs 74 Int cells. T. gondii-induced NLRP3 inflammasome activation was strongly associated with the phosphorylation of p38 MAPK; however, JNK1/2 had a weak effect. NLRP6 inflammasome activation was not related to the MAPK pathway in FHs 74 Int cells. CONCLUSIONS: This study highlighted the expression profiles of NLRs and unraveled the underlying mechanisms of NLRP3 inflammasome activation in T. gondii-infected FHs 74 Int cells. These findings may contribute to understanding of the mucosal and innate immune responses induced by the NLRs and inflammasomes during T. gondii infection in FHs 74 Int cells.
Asunto(s)
Células Epiteliales/parasitología , Regulación de la Expresión Génica/inmunología , Inmunidad Innata , Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteínas NLR/genética , Línea Celular , Humanos , Inflamasomas/inmunología , Intestino Delgado/citología , Intestino Delgado/parasitología , Proteínas NLR/clasificación , Proteínas NLR/inmunología , ARN MensajeroRESUMEN
The plant immune system involves cell-surface receptors that detect intercellular pathogen-derived molecules, and intracellular receptors that activate immunity upon detection of pathogen-secreted effector proteins that act inside the plant cell. Immunity mediated by surface receptors has been extensively studied1, but that mediated by intracellular receptors has rarely been investigated in the absence of surface-receptor-mediated immunity. Furthermore, interactions between these two immune pathways are poorly understood. Here, by activating intracellular receptors without inducing surface-receptor-mediated immunity, we analyse interactions between these two distinct immune systems in Arabidopsis. Pathogen recognition by surface receptors activates multiple protein kinases and NADPH oxidases, and we find that intracellular receptors primarily potentiate the activation of these proteins by increasing their abundance through several mechanisms. Likewise, the hypersensitive response that depends on intracellular receptors is strongly enhanced by the activation of surface receptors. Activation of either immune system alone is insufficient to provide effective resistance against the bacterial pathogen Pseudomonas syringae. Thus, immune pathways activated by cell-surface and intracellular receptors in plants mutually potentiate to activate strong defences against pathogens. These findings reshape our understanding of plant immunity and have broad implications for crop improvement.
Asunto(s)
Arabidopsis/inmunología , Proteínas NLR/inmunología , Inmunidad de la Planta/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Arabidopsis/citología , Arabidopsis/microbiología , Muerte Celular , NADPH Oxidasas/metabolismo , Células Vegetales/inmunología , Células Vegetales/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Proteínas Quinasas/metabolismo , Pseudomonas fluorescens/inmunología , Pseudomonas syringae/inmunología , Pseudomonas syringae/patogenicidad , Transducción de Señal/inmunologíaRESUMEN
The plant immune system is fundamental for plant survival in natural ecosystems and for productivity in crop fields. Substantial evidence supports the prevailing notion that plants possess a two-tiered innate immune system, called pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). PTI is triggered by microbial patterns via cell surface-localized pattern-recognition receptors (PRRs), whereas ETI is activated by pathogen effector proteins via predominantly intracellularly localized receptors called nucleotide-binding, leucine-rich repeat receptors (NLRs)1-4. PTI and ETI are initiated by distinct activation mechanisms and involve different early signalling cascades5,6. Here we show that Arabidopsis PRR and PRR co-receptor mutants-fls2 efr cerk1 and bak1 bkk1 cerk1 triple mutants-are markedly impaired in ETI responses when challenged with incompatible Pseudomonas syrinage bacteria. We further show that the production of reactive oxygen species by the NADPH oxidase RBOHD is a critical early signalling event connecting PRR- and NLR-mediated immunity, and that the receptor-like cytoplasmic kinase BIK1 is necessary for full activation of RBOHD, gene expression and bacterial resistance during ETI. Moreover, NLR signalling rapidly augments the transcript and/or protein levels of key PTI components. Our study supports a revised model in which potentiation of PTI is an indispensable component of ETI during bacterial infection. This revised model conceptually unites two major immune signalling cascades in plants and mechanistically explains some of the long-observed similarities in downstream defence outputs between PTI and ETI.
Asunto(s)
Arabidopsis/inmunología , Proteínas NLR/inmunología , Inmunidad de la Planta/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Arabidopsis/genética , Arabidopsis/microbiología , Proteínas de Arabidopsis/metabolismo , NADPH Oxidasas/metabolismo , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Proteínas Serina-Treonina Quinasas/metabolismo , Pseudomonas syringae/inmunología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/inmunologíaRESUMEN
With the increasing volume of high-throughput sequencing data from a variety of omics techniques in the field of plant-pathogen interactions, sorting, retrieving, processing and visualizing biological information have become a great challenge. Within the explosion of data, machine learning offers powerful tools to process these complex omics data by various algorithms, such as Bayesian reasoning, support vector machine and random forest. Here, we introduce the basic frameworks of machine learning in dissecting plant-pathogen interactions and discuss the applications and advances of machine learning in plant-pathogen interactions from molecular to network biology, including the prediction of pathogen effectors, plant disease resistance protein monitoring and the discovery of protein-protein networks. The aim of this review is to provide a summary of advances in plant defense and pathogen infection and to indicate the important developments of machine learning in phytopathology.