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

Activation of plant immunity through conversion of a helper NLR homodimer into a resistosome DOI Creative Commons
Muniyandi Selvaraj, AmirAli Toghani, Hsuan Pai

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(10), P. e3002868 - e3002868

Published: Oct. 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.

Language: Английский

Citations

11
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.

Science Advances, Journal Year: 2024, Volume and Issue: 10(45)

Published: Nov. 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.

Language: Английский

Citations

10
Inflammasome Molecular Insights in Autoimmune Diseases DOI Creative Commons

Monica Neamţu,

Veronica Bild, Alexandru Vasincu

et al.

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(4), P. 3502 - 3532

Published: April 18, 2024

Autoimmune diseases (AIDs) emerge due to an irregular immune response towards self- and non-self-antigens. Inflammation commonly accompanies these conditions, with inflammatory factors inflammasomes playing pivotal roles in their progression. Key concepts molecular biology, inflammation, mimicry are crucial understanding AID development. Exposure foreign antigens can cause potentially leading AIDs through triggered by cross-reactive epitopes. Molecular emerges as a key mechanism which infectious or chemical agents trigger autoimmunity. In certain susceptible individuals, autoreactive T B cells may be activated antigen resemblances between self-peptides. Chronic typically driven abnormal responses, is strongly associated pathogenesis. Inflammasomes, vital cytosolic multiprotein complexes assembled infections stress, activating processes macrophages. characterized prolonged tissue injury repair cycles, significantly damage tissues, thereby increasing the risk of AIDs. Inhibiting inflammasomes, particularly autoinflammatory disorders, has garnered significant interest, pharmaceutical advancements targeting cytokines showing promise management.

Language: Английский

Citations

9
The nucleotide‐binding domain of NRC‐dependent disease resistance proteins is sufficient to activate downstream helper NLR oligomerization and immune signaling DOI Creative Commons
Mauricio P. Contreras, Hsuan Pai, Rebecca Thompson

et al.

New Phytologist, Journal Year: 2024, Volume and Issue: 243(1), P. 345 - 361

Published: May 17, 2024

Summary Nucleotide‐binding domain and leucine‐rich repeat (NLR) proteins with pathogen sensor activities have evolved to initiate immune signaling by activating helper NLRs. However, the mechanisms underpinning NLR activation NLRs remain poorly understood. Although coiled coil (CC) type such as Potato virus X disease resistance protein Rx been shown activate oligomerization of their downstream helpers NRC2, NRC3 NRC4, domains involved in sensor–helper are not known. Here, we used Agrobacterium tumefaciens ‐mediated transient expression Nicotiana benthamiana show that nucleotide‐binding (NB) within NB‐ARC is necessary sufficient for In addition, NB Gpa2 (cyst nematode resistance), Rpi‐amr1, Rpi‐amr3 (oomycete resistance) Sw‐5b (virus also respective NRC helpers. Using lettuce ( Lactuca sativa ), (both full length or truncation) its NRC2 form a minimal functional unit can be transferred from solanaceous plants (lamiids) Campanulid species. Our results challenge prevailing paradigm exclusively signal via N‐terminal reveal activity NRC‐dependent We propose model which perceive status upstream sensors.

Language: Английский

Citations

9
Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis DOI Creative Commons
Abhimanu Pandey, Zheyi Li,

Manjul Gautam

et al.

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Summary Inflammasomes are multi‐protein complexes that assemble within the cytoplasm of mammalian cells in response to pathogen‐associated molecular patterns (PAMPs) or damage‐associated (DAMPs), driving secretion pro‐inflammatory cytokines IL‐1β and IL‐18, pyroptosis. The best‐characterized inflammasome NLRP3, NAIP‐NLRC4, NLRP1, AIM2, Pyrin canonical caspase‐1‐containing inflammasomes, caspase‐11 non‐canonical inflammasome. Newer sensor proteins have been identified, including NLRP6, NLRP7, NLRP9, NLRP10, NLRP11, NLRP12, CARD8, MxA. These sensors can sense PAMPs from bacteria, viruses protozoa, DAMPs form mitochondrial damage, ROS, stress heme. mechanisms action, physiological relevance, consequences human diseases, avenues for therapeutic intervention these novel inflammasomes beginning be realized. Here, we discuss emerging their putative activation mechanisms, signaling pathways, roles health disease.

Language: Английский

Citations

9
Role of macrophage in intervertebral disc degeneration DOI Creative Commons

Yiming Dou,

Yiming Zhang, Yang Liu

et al.

Bone Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 23, 2025

Language: Английский

Citations

1
NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury DOI Creative Commons

Yuzi Jin,

Joshua S. Fleishman,

Yudong Ma

et al.

Drug Design Development and Therapy, Journal Year: 2025, Volume and Issue: Volume 19, P. 1025 - 1041

Published: Feb. 1, 2025

Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy injury (SIMI), is a common complication of sepsis and associated with poor outcomes. However, the pathogenesis molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds inhibit NLRP3-associated pyroptosis may exert therapeutic effects against In this review, we first outlined principal elements NLRP3 signaling cascade summarized recent studies highlighting how activation contributes We selective small-molecule modulators function inhibitors delineated their action attenuate Finally, discuss major limitations current paradigm propose possible strategies overcome them. This review highlights pharmacological inhibition promising strategy.

Language: Английский

Citations

1
Targeting NLRC5 in cardiomyocytes protects postinfarction cardiac injury by enhancing autophagy flux through the CAVIN1/CAV1 axis DOI Creative Commons
Luo Gu, Sibo Wang, Liuhua Zhou

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 23, 2025

Language: Английский

Citations

1
A cell wall-associated kinase phosphorylates NLR immune receptor to negatively regulate resistosome formation DOI
Chenchen Zhong, Wenli Li, Xinyu Zhang

et al.

Nature Plants, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Language: Английский

Citations

1
CARD-like domains mediate anti-phage defense in bacterial gasdermin systems DOI Creative Commons
Tanita Wein,

Alex G. Johnson,

Adi Millman

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 29, 2023

Caspase recruitment domains (CARDs) and pyrin are important facilitators of inflammasome activity pyroptosis. Upon pathogen recognition by NLR proteins, CARDs recruit activate caspases, which, in turn, gasdermin pore forming proteins to induce pyroptotic cell death. Here we show that CARD-like present defense systems protect bacteria against phage. The bacterial CARD is essential for protease-mediated activation certain gasdermins, which promote death once phage infection recognized. We further multiple anti-phage utilize a variety effectors. find these triggered conserved immune evasion protein phages use overcome the system RexAB, demonstrating inhibiting one can another. also detect with predicted structure inhibit CARD-containing system. Our results suggest represent an ancient component innate from humans, CARD-dependent gasdermins organisms across tree life.

Language: Английский

Citations

22