NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation

Andreeva, Liudmila; David, Liron; Rawson, Shaun; Shen, Chen; Pasricha, Teerithveen; Pelegrı́n, Pablo; Wu, Hao

doi:10.1016/j.cell.2021.11.011

Cited by 155 publications

(217 citation statements)

References 74 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…Asp 21 is at the beginning of helix 2 and not involved in any intermolecular salt bridge or hydrogen bond formation. The side chain is facing Asp 60 (interface IIa) and Gln 45 (IIIa) of an adjacent molecule at 5.8 and 6.1 Å distance, respectively. The mutation to the larger histidine may enhance the interaction to these two residues, forming additional hydrogen bonds in these two interfaces (fig.…”

Section: Discussionmentioning

confidence: 99%

“…It can also be envisioned that topological constraints allow only one growth and PYD transition direction. Inactive NLRP3 forms a pentamer or hexamer of dimers with the PYDs shielded in a hollow sphere ( 44 , 45 ). Release of the PYDs upon activation, directing the C termini of the PYDs toward the core assembly, would expose the b-sides of the PYDs for filament extension.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation

et al. 2022

View full text Add to dashboard Cite

Inflammasomes sense intrinsic and extrinsic danger signals to trigger inflammatory responses and pyroptotic cell death. Homotypic pyrin domain (PYD) interactions of inflammasome forming nucleotide-binding oligomerization domain (NOD)–like receptors with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) mediate oligomerization into filamentous assemblies. We describe the cryo–electron microscopy (cryo-EM) structure of the human NLRP3 PYD filament and identify a pattern of highly polar interface residues that form the homomeric interactions leading to characteristic filament ends designated as A- and B-ends. Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3 PYD nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. Notably, NLRP3 and ASC PYD filaments exhibit the same symmetry in rotation and axial rise per subunit, allowing a continuous transition between NLRP3 and ASC. Integrating the directionality of filament growth, we present a molecular model of the ASC speck consisting of active NLRP3, ASC, and Caspase-1 proteins.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The association of NLRP3 with these organelles indicates that NLRP3 may have an ability to bind membranes. This is confirmed by a structural study which shows that both overexpressed and endogenous NLRP3 is predominantly membrane bound and that membrane binding is critical for NLRP3 double-ring cage formation by serving as a scaffolding platform ( 20 ).…”

Section: Association Of Nlrp3 Inflammasome With Er Mitochondria and G...mentioning

confidence: 71%

“…They further show that different NLRP3 stimuli promote dispersion of the trans-Golgi network (TGN) and the negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) exposed on the dispersed TGN (dTGN) recruit NLRP3 to form multiple puncta which induce ASC polymerization and subsequent inflammasome activation ( 10 ). A recent structural study reveals that full-length mouse NLRP3 forms an oligomeric double-ring cage via a LRR-LRR interaction, which is required for the formation of dTGN vesicles, providing structural insights into NLRP3-induced TGN dispersion into vesicles ( 20 ). The stimulus-induced NLRP3 recruitment to and aggregation at dTGN can also be seen in primary ASC-deficient bone marrow-derived macrophages (BMDMs), indicating that, in response to diverse stimuli, recruitment of NLRP3 to dTGN may be an early and common cellular event that leads to NLRP3 aggregation before the final assembly and activation ( 10 ).…”

Section: Association Of Nlrp3 Inflammasome With Er Mitochondria and G...mentioning

confidence: 99%

Inflammasome Meets Centrosome: Understanding the Emerging Role of Centrosome in Controlling Inflammasome Activation

Zhang

Jiang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Inflammasomes are multi-protein platforms that are assembled in response to microbial and danger signals to activate proinflammatory caspase-1 for production of active form of IL-1β and induction of pyroptotic cell death. Where and how an inflammasome is assembled in cells has remained controversial. While the endoplasmic reticulum, mitochondria and Golgi apparatus have been reported to be associated with inflammasome assembly, none of these sites seems to match the morphology, number and size of activated inflammasomes that are microscopically observable as one single perinuclear micrometer-sized punctum in each cell. Recently, emerging evidence shows that NLRP3 and pyrin inflammasomes are assembled, activated and locally regulated at the centrosome, the major microtubule organizing center in mammalian cells, elegantly accounting for the singularity, size and perinuclear location of activated inflammasomes. These new exciting findings reveal the previously unappreciated importance of the centrosome in controlling inflammasome assembly and activation as well as inflammasome-related diseases.

show abstract

“…Of particular interest is the destabilization of lysosomes and reactive oxygen species that is caused by aggregates such as monosodium urate and silica crystals [ 39 , 40 , 41 ], which will be described in detail later. In the inactive state, NLRP3 was recently discovered to be present as an inactive oligomer [ 42 , 43 ]. Upon activation, NLRP3 binds NEK7 [ 44 , 45 , 46 ], and this interaction forces NLRP3 to a semi-activated state [ 47 ].…”

Section: The Inflammasomes Multifacial Protein Inflammatory Complexesmentioning

confidence: 99%

The Role of Inflammasomes in Osteoarthritis and Secondary Joint Degeneration Diseases

Roškar

Hafner-Bratkovič

2022

Life

View full text Add to dashboard Cite

Osteoarthritis is age-related and the most common form of arthritis. The main characteristics of the disease are progressive loss of cartilage and secondary synovial inflammation, which finally result in pain, joint stiffness, and functional disability. Similarly, joint degeneration is characteristic of systemic inflammatory diseases such as rheumatoid arthritis and gout, with the associated secondary type of osteoarthritis. Studies suggest that inflammation importantly contributes to the progression of the disease. Particularly, cytokines TNFα and IL-1β drive catabolic signaling in affected joints. IL-1β is a product of inflammasome activation. Inflammasomes are inflammatory multiprotein complexes that propagate inflammation in various autoimmune and autoinflammatory conditions through cell death and the release of inflammatory cytokines and damage-associated molecule patterns. In this article, we review genetic, marker, and animal studies that establish inflammasomes as important drivers of secondary arthritis and discuss the current evidence for inflammasome involvement in primary osteoarthritis. The NLRP3 inflammasome has a significant role in the development of secondary osteoarthritis, and several studies have provided evidence of its role in the development of primary osteoarthritis, while other inflammasomes cannot be excluded. Inflammasome-targeted therapeutic options might thus provide a promising strategy to tackle these debilitating diseases.

show abstract

NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation

Cited by 155 publications

References 74 publications

Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation

Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation

Inflammasome Meets Centrosome: Understanding the Emerging Role of Centrosome in Controlling Inflammasome Activation

The Role of Inflammasomes in Osteoarthritis and Secondary Joint Degeneration Diseases

Contact Info

Product

Resources

About