WNK1 links ionic signals to microtubule dynamics to control pyrin inflammasome assembly.

WNK1 [with no lysine (K)] is a chloride- and potassium-sensitive kinase that regulates cellular ion homeostasis. Although WNK1 negatively regulates the NLRP3 and AIM2 inflammasomes, its role in pyrin inflammasome activation has remained unknown. Here, we identify WNK1 as a critical regulator of pyrin inflammasome assembly. In macrophages, genetic or pharmacologic inhibition of WNK1 suppresses pyrin activation without affecting pyrin dephosphorylation, demonstrating that WNK1 acts downstream of the canonical licensing step. This function occurs largely independently of the canonical SPAK/OXSR1 pathway. Mechanistically, WNK1 regulates microtubule dynamics: Its inhibition stabilizes microtubules, reduces plus-end growth, and impairs pyrin inflammasome assembly. Extracellular ionic conditions bidirectionally regulate this pathway, with hypotonic stress enhancing WNK1 activity and pyrin activation, whereas elevated extracellular potassium chloride suppresses WNK1 activity and inhibits pyrin assembly independently of osmotic stress. Together, these findings define an ion-sensitive WNK1-microtubule axis linking ionic signals to cytoskeletal dynamics to control pyrin inflammasome assembly and explain how WNK1 exerts opposing effects on distinct inflammasome pathways.