Structural basis of NLR activation and innate immune signalling in plants

AbstractAnimals and plants have NLRs (nucleotide-binding leucine-rich repeat receptors) that recognize the presence of pathogens and initiate innate immune responses. In plants, there are three types of NLRs distinguished by their N-terminal domain: the CC (coiled-coil) domain NLRs, the TIR (Toll/interleukin-1 receptor) domain NLRs and the RPW8 (resistance to powdery mildew 8)-like coiled-coil domain NLRs. CC-NLRs (CNLs) and TIR-NLRs (TNLs) generally act as sensors of effectors secreted by pathogens, while RPW8-NLRs (RNLs) signal downstream of many sensor NLRs and are called helper NLRs. Recent studies have revealed three dimensional structures of a CNL (ZAR1) including its inactive, intermediate and active oligomeric state, as well as TNLs (RPP1 and ROQ1) in their active oligomeric states. Furthermore, accumulating evidence suggests that members of the family of lipase-like EDS1 (enhanced disease susceptibility 1) proteins, which are uniquely found in seed plants, play a key role in providing a link between sensor NLRs and helper NLRs during innate immune responses. Here, we summarize the implications of the plant NLR structures that provide insights into distinct mechanisms of action by the different sensor NLRs and discuss plant NLR-mediated innate immune signalling pathways involving the EDS1 family proteins and RNLs.

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In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses

PLoS ONE ◽

10.1371/journal.pone.0187880 ◽

2017 ◽

Vol 12 (11) ◽

pp. e0187880 ◽

Cited By ~ 39

Author(s):

Ying Chen ◽

Wenda Zhou ◽

Terrence Roh ◽

Mary K. Estes ◽

David L. Kaplan

Keyword(s):

Immune Responses ◽

Intestinal Epithelium ◽

Three Dimensional ◽

Innate Immune ◽

Innate Immune Responses ◽

Tissue Model ◽

Small Intestinal Epithelium ◽

Small Intestinal

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ILT7 activation and plasmacytoid dendritic cell response are governed by BST2 determinants that are structurally-distinct

10.1101/557116 ◽

2019 ◽

Author(s):

Mariana G. Bego ◽

Nolwenn Miguet ◽

Alexandre Laliberté ◽

Nicolas Aschman ◽

Francine Gerard ◽

...

Keyword(s):

Immune Responses ◽

Plasmacytoid Dendritic Cell ◽

Coiled Coil ◽

Terminal Region ◽

Innate Immune ◽

Innate Immune Responses ◽

Structural Requirements ◽

Coiled Coil Region ◽

Binding Surface ◽

Trigger Receptor

AbstractThe interaction of the human pDC receptor ILT7 with its ligand, BST2, significantly regulates pDC’s TLR-induced innate immune responses. This interaction has critical biological consequences, yet, its structural requirements are not fully characterized. The BST2 ectodomain can be divided in structurally and functionally distinct regions; while the coiled-coil region contains a newly-defined ILT7 binding surface, the N-terminal region appears to negatively modulate ILT7 activation. A stable BST2 homodimer binds to ILT7 but post-binding events associated to the unique BST2 coiled-coil plasticity are required to trigger receptor signaling. Hence, BST2 with an unstable or with a rigid coiled-coil fails to activate ILT7, whereas mutations in the N-terminal region enhance activation. Importantly, the biological relevance of these newly defined domains of BST2 is underscored by the identification of mutations with opposed potential to activate ILT7, which are selected under pathological malignant conditions.

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Toll-like Receptors Induce a Phagocytic Gene Program through p38

Journal of Experimental Medicine ◽

10.1084/jem.20031237 ◽

2003 ◽

Vol 199 (1) ◽

pp. 81-90 ◽

Cited By ~ 267

Author(s):

Sean E. Doyle ◽

Ryan M. O'Connell ◽

Gustavo A. Miranda ◽

Sagar A. Vaidya ◽

Edward K. Chow ◽

...

Keyword(s):

Immune Responses ◽

Interleukin 1 ◽

Innate Immune ◽

Myeloid Differentiation ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Evolutionarily Conserved ◽

Myeloid Differentiation Factor ◽

The Relationship ◽

Number Of Bacteria

Toll-like receptor (TLR) signaling and phagocytosis are hallmarks of macrophage-mediated innate immune responses to bacterial infection. However, the relationship between these two processes is not well established. Our data indicate that TLR ligands specifically promote bacterial phagocytosis, in both murine and human cells, through induction of a phagocytic gene program. Importantly, TLR-induced phagocytosis of bacteria was found to be reliant on myeloid differentiation factor 88–dependent signaling through interleukin-1 receptor–associated kinase-4 and p38 leading to the up-regulation of scavenger receptors. Interestingly, individual TLRs promote phagocytosis to varying degrees with TLR9 being the strongest and TLR3 being the weakest inducer of this process. We also demonstrate that TLR ligands not only amplify the percentage of phagocytes uptaking Escherichia coli, but also increase the number of bacteria phagocytosed by individual macrophages. Taken together, our data describe an evolutionarily conserved mechanism by which TLRs can specifically promote phagocytic clearance of bacteria during infection.

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Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin

Journal of Experimental Medicine ◽

10.1084/jem.20041836 ◽

2005 ◽

Vol 201 (1) ◽

pp. 19-25 ◽

Cited By ~ 412

Author(s):

Cevayir Coban ◽

Ken J. Ishii ◽

Taro Kawai ◽

Hiroaki Hemmi ◽

Shintaro Sato ◽

...

Keyword(s):

Immune Responses ◽

Immune Activation ◽

Interleukin 1 ◽

Innate Immune ◽

Dependent Manner ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Innate Immune Activation

Malaria parasites within red blood cells digest host hemoglobin into a hydrophobic heme polymer, known as hemozoin (HZ), which is subsequently released into the blood stream and then captured by and concentrated in the reticulo-endothelial system. Accumulating evidence suggests that HZ is immunologically active, but the molecular mechanism(s) through which HZ modulates the innate immune system has not been elucidated. This work demonstrates that HZ purified from Plasmodium falciparum is a novel non-DNA ligand for Toll-like receptor (TLR)9. HZ activated innate immune responses in vivo and in vitro, resulting in the production of cytokines, chemokines, and up-regulation of costimulatory molecules. Such responses were severely impaired in TLR9−/− and myeloid differentiation factor 88 (MyD88)−/−, but not in TLR2, TLR4, TLR7, or Toll/interleukin 1 receptor domain–containing adaptor-inducing interferon β−/− mice. Synthetic HZ, which is free of the other contaminants, also activated innate immune responses in vivo in a TLR9-dependent manner. Chloroquine (CQ), an antimalarial drug, abrogated HZ-induced cytokine production. These data suggest that TLR9-mediated, MyD88-dependent, and CQ-sensitive innate immune activation by HZ may play an important role in malaria parasite–host interactions.

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Geranylgeraniol Suppresses the Expression of IRAK1 and TRAF6 to Inhibit NFκB Activation in Lipopolysaccharide-Induced Inflammatory Responses in Human Macrophage-Like Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20092320 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2320 ◽

Cited By ~ 4

Author(s):

Puspo E. Giriwono ◽

Hitoshi Shirakawa ◽

Yusuke Ohsaki ◽

Shoko Sato ◽

Yukihide Aoyama ◽

...

Keyword(s):

Immune Responses ◽

Nuclear Factor Kappa B ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Tumor Necrosis Factor Receptor ◽

Innate Immune ◽

Human Macrophage ◽

Signaling Proteins ◽

Innate Immune Responses ◽

Necrosis Factor

Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. We found that GGOH decreased the expression of lipopolysaccharide (LPS)-induced inflammatory genes in human macrophage-like THP-1 cells. Furthermore, we observed that the suppression of NFκB signaling proteins, in particular interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), occurred in GGOH-treated cells prior to LPS stimulation, suggesting an immunomodulatory effect. These results indicate that GGOH may modulate and help prevent excessive NFκB activation that can lead to numerous diseases.

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Direct pathogen-induced assembly of an NLR immune receptor complex to form a holoenzyme

Science ◽

10.1126/science.abe3069 ◽

2020 ◽

Vol 370 (6521) ◽

pp. eabe3069 ◽

Cited By ~ 5

Author(s):

Shoucai Ma ◽

Dmitry Lapin ◽

Li Liu ◽

Yue Sun ◽

Wen Song ◽

...

Keyword(s):

Immune Responses ◽

Active Sites ◽

Interleukin 1 ◽

Innate Immune ◽

Innate Immune Responses ◽

Cryo Electron Microscopy ◽

Effector Recognition ◽

Functional Analyses ◽

Hyaloperonospora Arabidopsidis ◽

Jelly Roll

Direct or indirect recognition of pathogen-derived effectors by plant nucleotide-binding leucine-rich repeat (LRR) receptors (NLRs) initiates innate immune responses. The Hyaloperonospora arabidopsidis effector ATR1 activates the N-terminal Toll–interleukin-1 receptor (TIR) domain of Arabidopsis NLR RPP1. We report a cryo–electron microscopy structure of RPP1 bound by ATR1. The structure reveals a C-terminal jelly roll/Ig-like domain (C-JID) for specific ATR1 recognition. Biochemical and functional analyses show that ATR1 binds to the C-JID and the LRRs to induce an RPP1 tetrameric assembly required for nicotinamide adenine dinucleotide hydrolase (NADase) activity. RPP1 tetramerization creates two potential active sites, each formed by an asymmetric TIR homodimer. Our data define the mechanism of direct effector recognition by a plant NLR leading to formation of a signaling-active holoenzyme.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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