BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

Inflammation is required for host defense as well as wound healing but wields enormous destructive potential, highlighting the need for multiple ‘checks and balances’ . The NLRP3 inflammasome, a pivotal molecular machine for the maturation of IL-1 family pro-inflammatory cytokines , is controlled by accessory proteins , post-translational modifications , localization and oligomerization . How these factors act in concert is unclear. We show that the established drug target and NLRP3 regulator, Bruton’s Tyrosine Kinase (BTK) , integrates several levels of regulation to boost inflammasome activity: by directly phosphorylating four conserved tyrosine residues in the polybasic linker region of NLRP3, BTK weakens the interaction of NLRP3 with Golgi phospholipids and may thus guide NLRP3 localization. BTK activity also promotes NLRP3 oligomerization and subsequent formation of inflammasomes. As NLRP3 tyrosine modification impacts on IL-1β release, we propose a novel BTK- and charge-mediated molecular phospho-switch to contribute to NLRP3 regulation. Collectively, our study highlights BTK as a ‘multi-layer regulator’ of the inflammasome and NLRP3 multi-tyrosine phosphorylation as a therapeutic target for restricting excess inflammation.