Scientists discover how immune cells sense danger through potassium loss
Researchers have identified the molecular mechanism by which cells detect potassium leakage and trigger inflammation—a process linked to heart disease, diabetes, and neurodegeneration. The discovery could enable drug developers to design more targeted anti-inflammatory therapies by directly modulating this newly understood sensor.
Originaltitel: NLRP3 acts as a direct sensor of intracellular potassium ions
Summary The NLRP3 inflammasome is a sentinel of cellular homeostasis, and its activation triggers the assembly of a molecular machinery that drives inflammation in infection, cardiovascular, metabolic, and neurodegenerative diseases. The majority of the many triggers known to activate NLRP3 are believed to induce potassium ion (K + ) efflux from the cell as a fundamental danger signal for compromised cellular integrity. However, it has remained unclear how a reduction in intracellular K + concentration is mechanistically translated into conformational changes in NLRP3 that promote inflammasome assembly, interleukin (IL)-1 release, and cell death. Here, we provide evidence that alterations in K + levels directly regulate the conformation of the NLRP3 protein. In cell-free lysates derived from cell lines and primary blood immune cells high K + concentrations stabilized a compact, protease-resistant structure resembling inhibitor-bound NLRP3, whereas low K + conditions or the presence of a K + chelator favored an open, more flexible and protease-accessible conformation. Notably, human NLRP3 remained responsive to K + even when exogenously expressed in macrophage-like Drosophila cells or purified as recombinant protein. This indicates that K + sensing occurs independently of cellular co-factors and is consistent with direct ion coordination. Of note, stimulation with the K + -independent NLRP3 agonist CL097 failed to recapitulate the conformational transition caused by K + efflux inducer, nigericin. Moreover, pathogenic gain-of-function mutant variants of NLRP3 constitutively resembled the open and flexible protease-accessible conformation. Mapping K + -interactions by high-performance computation suggested that K + ions populate the nucleotide binding pocket of the FISNA-NACHT module of individual NLRP3 chains but also stabilize face-to-face interactions within inactive oligomeric ‘cage’ assemblies via the NACHT-adjacent acidic loop. Collectively, our findings enable us to propose a mechanistic model of how intracellular K + ions preclude NLRP3 activation prior to efflux and thus how NLRP3 responds to cellular danger as a direct K + sensing protein.