A disease resistance protein triggers oligomerization of its NLR helper into a hexameric resistosome to mediate innate immunity DOI Creative Commons
Jogi Madhuprakash, AmirAli Toghani, Mauricio P. Contreras

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 19, 2024

Abstract NRCs are essential helper NLR (nucleotide-binding domain and leucine-rich repeat) proteins that execute the immune response triggered by disease resistance proteins, also known as sensor NLRs. The structure of resting state NbNRC2 was recently revealed to be a homodimer. However, sensor-activated has not yet been elucidated. In this study, we used cryo-EM determine NbNRC2, which forms hexameric inflammasome-like resistosome. To confirm functional significance hexamer, mutagenized interfaces involved in oligomerization found mutations three nucleotide-binding interface residues abolish signalling. Comparative structural analyses between homodimer homohexamer significant rearrangements before after activation, providing insights into activation mechanisms. Furthermore, comparisons hexamer previously reported CC-NLR pentameric assemblies features allow for integration an additional protomer. We assess released AlphaFold 3 prediction activated oligomers. This allows high-confidence modelling N-terminal α 1-helices other CC-NLRs, region proven difficult fully resolve using approaches. Overall, our work sheds light on biochemical mechanisms underpinning expands understanding diversity.

Language: Английский

The NLRP3 inflammasome: contributions to inflammation-related diseases DOI Creative Commons
Ying Chen,

Xingyan Ye,

Germaine Escames

et al.

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: June 27, 2023

The NOD-like receptor protein 3 (NLRP3) inflammasome is a complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines interleukin (IL)-1β IL-18. Multiple studies have demonstrated importance of NLRP3 in development inflammation-related diseases, including arthritis, Alzheimer's disease, bowel other autoimmune autoinflammatory diseases. This review first explains activation regulatory mechanism inflammasome. Secondly, we focus on role various Finally, look forward to new methods for targeting treat provide ideas clinical treatment.

Language: Английский

Citations

129
Mechanistic insights from inflammasome structures DOI
Jianing Fu, Kate Schroder, Hao Wu

et al.

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: 24(7), P. 518 - 535

Published: Feb. 19, 2024

Language: Английский

Citations

64
The NLR family of innate immune and cell death sensors DOI Creative Commons
Balamurugan Sundaram, Rebecca E. Tweedell, Sivakumar Prasanth Kumar

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 674 - 699

Published: April 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.

Language: Английский

Citations

61
NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks DOI
Liron David, Jazlyn P. Borges, Louis Hollingsworth

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(9), P. 2224 - 2235.e16

Published: April 1, 2024

Language: Английский

Citations

53
NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation DOI Creative Commons
Balamurugan Sundaram, Pandian Nagakannan, Hee Jin Kim

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 4061 - 4077.e17

Published: June 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.

Language: Английский

Citations

44
Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities DOI
Ingo Hilgendorf, Stefan Frantz, Nikolaos G. Frangogiannis

et al.

Circulation Research, Journal Year: 2024, Volume and Issue: 134(12), P. 1718 - 1751

Published: June 6, 2024

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory fibrogenic cascades that ultimately result in formation a scar. After infarction, massive cardiomyocyte death releases broad range damage-associated molecular patterns initiate both myocardial systemic responses. TLRs (toll-like receptors) NLRs (NOD-like recognize (DAMPs) transduce downstream proinflammatory signals, leading to upregulation cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], interleukin-6) chemokines CCL2 [CC chemokine ligand 2]) recruitment neutrophils, monocytes, lymphocytes. Expansion diversification cardiac macrophages infarcted play major role clearance infarct from dead cells subsequent stimulation reparative pathways. Efferocytosis triggers induction release anti-inflammatory mediators restrain reaction set stage for fibroblasts vascular cells. Growth factor–mediated pathways, neurohumoral cascades, matricellular proteins deposited provisional matrix stimulate fibroblast proliferation myofibroblast conversion. Deposition well-organized collagen-based extracellular network protects catastrophic rupture attenuates ventricular dilation. Scar maturation requires signals inhibit activity prevent excessive fibrosis. Moreover, mature scar, neovessels acquire mural cell coat contributes stabilization microvascular network. Excessive, prolonged, or dysregulated accentuate adverse remodeling dysfunction. leukocytes can contribute arrhythmogenesis. Inflammatory pathways may be promising therapeutic targets attenuate failure progression arrhythmia generation patients surviving infarction.

Language: Английский

Citations

23
Innate immune activation in neurodegenerative diseases DOI
Sergio Castro‐Gomez, Michael T. Heneka

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 790 - 814

Published: April 1, 2024

Language: Английский

Citations

21
NOD-like Receptor Signaling Pathway in Gastrointestinal Inflammatory Diseases and Cancers DOI Open Access
Yujie Zhou,

Songyan Yu,

Wenyong Zhang

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14511 - 14511

Published: Sept. 25, 2023

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular proteins with a central role in innate adaptive immunity. As member of pattern recognition (PRRs), NLRs sense specific pathogen-associated molecular patterns, trigger numerous signaling pathways lead to the secretion various cytokines. In recent years, cumulative studies have revealed significant impacts gastrointestinal (GI) inflammatory diseases cancers. Deciphering mechanism NLR may provide new opportunities for development therapeutic strategies related GI This review presents structures NLRs, summarizes advances regarding cancers describes comprehensive based on this pathway.

Language: Английский

Citations

23
Innate immune responses to RNA: sensing and signaling DOI Creative Commons
Xiaohan Luan, Lei Wang,

Guangji Song

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 25, 2024

Nucleic acids are among the most essential PAMPs (pathogen-associated molecular patterns). Animals have evolved numerous sensors to recognize nucleic and trigger immune signaling against pathogen replication, cellular stress cancer. Many sensor proteins (e.g., cGAS, AIM2, TLR9) signature of infection or responsible for innate response DNA. Remarkably, recent evidence demonstrates that cGAS-like receptors acquire ability sense RNA in some forms life. Compared with nucleic-acid sensing by responses based on various sensors, including RIG-I, MDA5, ADAR1, TLR3/7/8, OAS1, PKR, NLRP1/6, ZBP1, via a broad-spectrum axis. Importantly, new advances brought light potential clinical application targeting these pathways. Here, we highlight latest discoveries field. We also summarize activation regulatory mechanisms RNA-sensing signaling. In addition, discuss how is tightly controlled cells why disruption homeostasis linked disease.

Language: Английский

Citations

14
Physiological and immunological barriers in the lung DOI Creative Commons
Takahiro Kageyama, Takashi Ito, Shigeru Tanaka

et al.

Seminars in Immunopathology, Journal Year: 2024, Volume and Issue: 45(4-6), P. 533 - 547

Published: Jan. 1, 2024

Abstract The lungs serve as the primary organ for respiration, facilitating vital exchange of gases with bloodstream. Given their perpetual exposure to external particulates and pathogens, they possess intricate protective barriers. Cellular adhesion in is robustly maintained through tight junctions, adherens desmosomes. Furthermore, pulmonary system features a mucociliary clearance mechanism that synthesizes mucus transports it outside. This enriched chemical barriers like antimicrobial proteins immunoglobulin A (IgA). Additionally, complex immunological network comprising epithelial cells, neural immune cells plays pivotal role defense. comprehensive understanding these systems offers valuable insights into potential pathologies therapeutic interventions.

Language: Английский

Citations

12