The NLR family of innate immune and cell death sensors

Immunity, Год журнала: 2024, Номер 57(4), С. 674 - 699

Опубликована: Апрель 1, 2024

Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition that detect wide variety pathogenic and sterile triggers. Activation specific NLRs initiates pro- or anti-inflammatory signaling cascades the formation inflammasomes—multi-protein complexes induce caspase-1 activation to drive inflammatory cytokine maturation lytic cell death, pyroptosis. Certain inflammasomes act integral components larger death complexes—PANoptosomes—driving another form PANoptosis. Here, we review current understanding evolution, structure, function in health disease. We discuss concept NLR networks their roles driving immunity. An improved mechanistic may provide therapeutic strategies applicable across infectious diseases cancer.

Язык: Английский

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NLR receptors in plant immunity: making sense of the alphabet soup

EMBO Reports, Год журнала: 2023, Номер 24(10)

Опубликована: Авг. 21, 2023

Plants coordinately use cell-surface and intracellular immune receptors to perceive pathogens mount an response. Intracellular events of pathogen recognition are largely mediated by the nucleotide binding leucine rich-repeat (NLR) classes. Upon perception, NLRs trigger a potent broad-spectrum reaction, usually accompanied form programmed cell death termed hypersensitive Some plant act as multifunctional singleton which combine detection signaling. However, can also function in higher order pairs networks functionally specialized interconnected receptors. In this article, we cover basic aspects NLR biology with emphasis on networks. We highlight some recent advances structure, function, activation discuss emerging topics such modulator NLRs, suppression bioengineering. Multi-disciplinary approaches required disentangle how these receptor evolve. Answering questions holds potential deepen our understanding system unlock new era disease resistance breeding.

Язык: Английский

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NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation

Cell, Год журнала: 2024, Номер 187(15), С. 4061 - 4077.e17

Опубликована: Июнь 14, 2024

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated inflammatory infectious diseases, but little known about its function as innate immune sensor cell death regulator. Therefore, we screened for NLRC5's role in response infections, PAMPs, DAMPs, cytokines. We identified acts drive death, PANoptosis, specific ligands, including PAMP/heme heme/cytokine combinations. interacted NLRP12 PANoptosome components form complex, suggesting network forms similar those plants. Mechanistically, TLR signaling NAD+ levels regulated expression ROS production control death. Furthermore, NLRC5-deficient mice were protected hemolytic models, could be potential target.

Язык: Английский

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Oligomerization-mediated autoinhibition and cofactor binding of a plant NLR

Nature, Год журнала: 2024, Номер 632(8026), С. 869 - 876

Опубликована: Июнь 12, 2024

Abstract Nucleotide-binding leucine-rich repeat (NLR) proteins play a pivotal role in plant immunity by recognizing pathogen effectors 1,2 . Maintaining balanced immune response is crucial, as excessive NLR expression can lead to unintended autoimmunity 3,4 Unlike most NLRs, the required for cell death 2 (NRC2) belongs small group characterized constitutively high without self-activation 5 The mechanisms underlying NRC2 autoinhibition and activation are not yet understood. Here we show that Solanum lycopersicum (tomato) ( Sl NRC2) forms dimers tetramers higher-order oligomers at elevated concentrations. Cryo-electron microscopy shows an inactive conformation of these oligomers. Dimerization oligomerization only stabilize state but also sequester from assembling into active form. Mutations dimeric or interdimeric interfaces enhance pathogen-induced Nicotiana benthamiana cryo-electron structures unexpectedly inositol hexakisphosphate (IP 6 ) pentakisphosphate bound inner surface C-terminal domain NRC2, confirmed mass spectrometry. phosphate-binding site impair phosphate binding NRC2-mediated N. Our study indicates negative regulatory mechanism suggests phosphates cofactors NRCs.

Язык: Английский

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Plant NLR immunity activation and execution: a biochemical perspective

Open Biology, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 1, 2024

Plants deploy cell-surface and intracellular receptors to detect pathogen attack trigger innate immune responses. Inside host cells, families of nucleotide-binding/leucine-rich repeat (NLR) proteins serve as sensors or downstream mediators defence outputs cell death, which prevent disease. Established genetic underpinnings NLR-mediated immunity revealed various strategies plants adopt combat rapidly evolving microbial pathogens. The molecular mechanisms NLR activation signal transmission components controlling execution were less clear. Here, we review recent protein structural biochemical insights plant sensor signalling functions. When put together, the data show how different families, whether transducers, converge on nucleotide-based second messengers cellular calcium confer immunity. Although pathogen-activated NLRs in engage plant-specific machineries promote defence, comparisons with mammalian receptor counterparts highlight some shared working principles for across kingdoms.

Язык: Английский

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Activation of the helper NRC4 immune receptor forms a hexameric resistosome

Cell, Год журнала: 2024, Номер 187(18), С. 4877 - 4889.e15

Опубликована: Авг. 1, 2024

Язык: Английский

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Cytoplasmic calcium influx mediated by plant MLKLs confers TNL-triggered immunity

Cell Host & Microbe, Год журнала: 2024, Номер 32(4), С. 453 - 465.e6

Опубликована: Март 20, 2024

The plant homolog of vertebrate necroptosis inducer mixed-lineage kinase domain-like (MLKL) contributes to downstream steps in Toll-interleukin-1 receptor domain NLR (TNL)-receptor-triggered immunity. Here, we show that Arabidopsis MLKL1 (AtMLKL1) clusters into puncta at the plasma membrane upon TNL activation and this sub-cellular reorganization is dependent on signal transducer, EDS1. We find AtMLKLs confer TNL-triggered immunity parallel with RPW8-type HeLo-domain-containing NLRs (RNLs) AtMLKL N-terminal HeLo indispensable for both clustering. mediates cytoplasmic Ca

Язык: Английский

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Activation of plant immunity through conversion of a helper NLR homodimer into a resistosome

PLoS Biology, Год журнала: 2024, Номер 22(10), С. e3002868 - e3002868

Опубликована: Окт. 18, 2024

Nucleotide-binding domain and leucine-rich repeat (NLR) proteins can engage in complex interactions to detect pathogens execute a robust immune response via downstream helper NLRs. However, the biochemical mechanisms of NLR activation by upstream sensor NLRs remain poorly understood. Here, we show that coiled-coil NRC2 from Nicotiana benthamiana accumulates vivo as homodimer converts into higher-order oligomer upon its virus disease resistance protein Rx. The cryo-EM structure NbNRC2 resting state revealed intermolecular mediate formation contribute receptor autoinhibition. These dimerization interfaces have diverged between paralogous NRC insulate critical network nodes enable redundant pathways, possibly minimise undesired cross-activation evade pathogen suppression immunity. Our results expand molecular pointing transition homodimers oligomeric resistosomes.

Язык: Английский

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Two mitogen-activated protein kinase cascades in plant immunity

Journal of Experimental Botany, Год журнала: 2024, Номер 75(8), С. 2256 - 2265

Опубликована: Янв. 18, 2024

Abstract The mitogen-activated protein kinase (MAPK/MPK) cascade is an important intercellular signaling module that regulates plant growth, development, reproduction, and responses to biotic abiotic stresses. A MAPK usually consists of a (MAPKKK/MEKK), (MAPKK/MKK/MEK), MAPK. well-characterized cascades in immunity date are the MEKK1-MKK1/2-MPK4 MAPKKK3/4/5-MKK4/5-MPK3/6 cascade. Recently, major breakthroughs have been made understanding molecular mechanisms associated with regulation immune by both these cascades. In this review, we highlight most recent advances role activating defense suppressing or fine-tuning signaling. We also discuss which plants stabilize maintain activation during Based on reveal complexity importance cascade, tightly controlled their interacting partners substrates, immunity.

Язык: Английский

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A disease resistance protein triggers oligomerization of its NLR helper into a hexameric resistosome to mediate innate immunity

Science Advances, Год журнала: 2024, Номер 10(45)

Опубликована: Ноя. 6, 2024

NRCs are essential helper NLR (nucleotide-binding domain and leucine-rich repeat) proteins that execute immune responses triggered by sensor NLRs. The resting state of NbNRC2 was recently shown to be a homodimer, but the sensor-activated remains unclear. Using cryo-EM, we determined structure NbNRC2, which forms hexameric inflammasome-like resistosome. Mutagenesis oligomerization interface abolished signaling, confirming functional significance Comparative structural analyses between homodimer homohexamer revealed substantial rearrangements, providing insights into activation mechanisms. Furthermore, comparisons hexamer previously reported CC-NLR pentameric assemblies features allowing an additional protomer integration. structure, assessed released AlphaFold 3 for predicting activated oligomers, revealing high-confidence modeling other amino-terminal α1 helices, region proven difficult resolve structurally. Overall, our work sheds light on mechanisms expands understanding diversity.

Язык: Английский

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