The kinesin motor KIF11 coordinates NLR localization and activation in the innate immune response

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) detect invading pathogens and danger-associated signals, but how their intracellular localization is controlled remains unclear. Through a genome-wide shRNA screen, we identified the kinesin-related motor protein KIF11 as a critical component of NLRC4-dependent innate immune responses. KIF11 interacts with the NOD of NLRC4, NLRP3, and NOD2 via its motor domain, and its inhibition attenuates these NLR-mediated immune responses. In vitro reconstitution assays revealed that KIF11 binds to and transports NLRs along microtubules, while immunocytochemical analyses showed their colocalization under resting conditions. KIF11 inhibition decreased the levels of microtubule-associated NLRs within their respective intracellular compartments. These findings uncover KIF11 as a common upstream component that orchestrates pre-stimulation NLR positioning and subsequent activation, providing a mechanistic link between cytoskeletal dynamics and innate immune signaling.