Caspase-1 activation within the NLRP3 inflammasome leads to IL-1beta maturation and pyroptosis. NLRP3 is activated by a diverse range of danger signals including ATP, monosodium urate (MSU) crystals, cholesterol crystals, and silica. The common intracellular signal that converges from all these stimuli to activate NLRP3 is:
- A Mitochondrial fission and release of cardiolipin
- B Potassium efflux from the cell ✓
- C Nuclear translocation of NF-kB p65 subunit
- D ER stress-induced ATF6 cleavage
Explanation
Despite the structural diversity of NLRP3 activators (ATP, MSU, cholesterol crystals, silica, amyloid beta, uric acid, nigericin), cytosolic potassium efflux is the common intracellular convergence signal required for NLRP3 inflammasome assembly. Reduction in intracellular K+ concentration below a threshold (~100 mM) directly relieves an autoinhibitory conformation of NLRP3, permitting its oligomerisation and recruitment of ASC adaptor and pro-caspase-1. ATP activates P2X7 receptors (which are K+ channels); pore-forming toxins and nigericin directly cause K+ efflux; crystals disrupt lysosomal membranes releasing cathepsin B which triggers K+ efflux. Blocking K+ efflux with high extracellular K+ inhibits virtually all NLRP3 activators, confirming it as the unifying signal.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.