A surprising link between the inflammasome and the centrosome

Abstract

Abstract The NLRP3 inflammasome is a multisubunit protein complex of the innate immune system that senses and responds to a broad range of cell-intrinsic, pro-inflammatory stimuli. Upon activation in non-mitotic cells, NLRP3 aggregates with the inflammasome subunits ASC and Caspase-1 to assemble a single perinuclear superstructure. However, the processes and mechanisms that orchestrate inflammasome assembly and drive pyroptosis are largely unknown. Here, we show that the inflammasome recruits and colocalizes with known centrosome-associated proteins, γ-Tubulin and Centrin, in a Caspase-1 dependent manner. While the NLRP3 inflammasome does not colocalize with the centrosome itself, we show that the inflammasome assembles in close proximity to the centrosome early after NLRP3 activation. Furthermore, inflammasome formation results in a breakdown of the microtubule network as well as decreased γ-Tubulin and Pericentrin staining at the centrosome. These observations are strengthened by our proteomic studies identifying >30 centrosomal interacting with NLRP3 and/or Caspase-1. One protein in particular is Nek7, a serine/threonine kinase required for the recruitment of γ-Tubulin and Pericentrin to the centrosome, suggesting that inflammasome activation phenocopies Nek7 loss. Finally, depletion of Nek7 inhibits pyroptotic cell death. Therefore, these data reveal a novel link between the inflammasome and centrosome, possibly bridged by NEK7, and provide mechanistic insight into inflammasome formation and pyroptosis.