NLRP3 Inflammasome Assembly Project
Bottom line: the NLRP3 inflammasome is a danger-sensing complex in which
the sensor NLRP3 recruits the adaptor PYCARD (ASC) to activate caspase-1, which
matures IL-1β and IL-18 and cleaves gasdermin D to open pyroptotic pores.
Scoped, not yet started as a project: this page lists ten candidate human genes
and the pathway architecture, but no project-specific review work has been
done. Three candidates already have complete reviews from other work (NLRP3,
CASP4 and GSDMD, 364 annotations between them; most removals are generic
protein binding rows, 24 of 25 on NLRP3), and the NLRP3 review proposes a
new GO term, inflammasome sensor activity, because GO:0140299 molecular
sensor activity requires binding the sensed molecule. The adaptor PYCARD, the effector
CASP1, CASP5, IL1B, IL18, NEK7 and BRCC3 have no gene folder. A draft
NLR signaling module already includes NLRP3,
PYCARD and CASP1 and is the natural home for an inflammasome model.
We scoped this because NLRP3 is a major therapeutic target and drives
autoinflammatory disease (CAPS) and inflammation in gout, atherosclerosis and
Alzheimer disease, and recent work on activation sites, post-translational
control and structure is likely to be under-represented in GO.
Overview
The NLRP3 inflammasome is a multiprotein complex that activates inflammatory caspases in response to diverse danger signals, leading to IL-1β/IL-18 release and pyroptotic cell death. Recent discoveries have clarified activation mechanisms and identified new regulators.
Model Species
Primary: Homo sapiens (human)
- Major therapeutic target
- Autoinflammatory disease relevance
Core Pathway Architecture
1. Sensor
- NLRP3 - NOD-like receptor, sensor component
2. Adaptor
- PYCARD (ASC) - Adaptor with PYD and CARD domains
3. Effector Caspases
- CASP1 - Caspase-1, cleaves pro-IL-1β
- CASP4/5 - Non-canonical inflammasome
4. Substrates/Outputs
- IL1B - Pro-inflammatory cytokine
- IL18 - Pro-inflammatory cytokine
- GSDMD - Gasdermin D, pore-forming executioner
5. Critical Regulators
- NEK7 - Essential NLRP3 activator (discovered 2016)
- BRCC3 - Deubiquitinase
- Various negative regulators
6. Priming/Licensing
- NFKB pathway - Transcriptional priming
Candidate Genes (~12-15)
| Gene | UniProt | Function |
|---|---|---|
| NLRP3 | Q96P20 | Sensor |
| PYCARD | Q9ULZ3 | ASC adaptor |
| CASP1 | P29466 | Effector caspase |
| CASP4 | P49662 | Non-canonical |
| CASP5 | P51878 | Non-canonical |
| GSDMD | P57764 | Pore formation |
| IL1B | P01584 | Cytokine |
| IL18 | Q14116 | Cytokine |
| NEK7 | Q8TDX7 | Essential activator |
| BRCC3 | P46736 | Deubiquitinase |
Key Recent Discoveries (2020+)
- Trans-Golgi network as NLRP3 activation site
- Post-translational modifications regulating assembly
- Structural basis of inflammasome assembly
- GSDMD pore structure
Disease Relevance
- CAPS (Cryopyrin-associated periodic syndromes)
- Gout, atherosclerosis
- Alzheimer's disease
- COVID-19 severity
Project Status
- [ ] Stub - needs gene folder setup
Slides
- Slides (Marp source: NLRP3_INFLAMMASOME-slides.md) — AI generated