Extra centrosomes induce PIDD1-mediated inflammation and Immunosurveillance
Unscheduled increases in cellular ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of centrosomes, the main microtubule organization center in animal cells. Supernumerary centrosomes are frequent in tumors, correlating with higher aggressiveness and poor prognosis. However, extra centrosomes also exert an onco-protective effect by activating the p53 network and eliciting cell cycle arrest. Here, we report that extra centrosomes, arising during unscheduled polyploidization or aberrant centriole biogenesis, induce activation of NF-?B signaling and sterile inflammation. This signaling requires the NEMO-PIDDOsome, a multi-protein complex composed of PIDD1, RIPK1, and NEMO/IKK?. Remarkably, the presence of supernumerary centrosomes suffices to induce a paracrine chemokine and cytokine profile, able to polarize macrophages into a pro-inflammatory phenotype. Furthermore, extra centrosomes, accumulating after cytokinesis failure, increase immunogenicity of cancer cells and render them more susceptible to NK-cell attack. Hence, extra centrosomes, the PIDDosome acts as a dual effector, able to engage not only the p53 network for cell cycle control but also NF-?B signaling to instruct innate immunity. Overall design: Primary mouse embryonic fibroblasts (MEF) were treated with the Aurora kinase inhibitor ZM447439, 2mM for 72h, in WT or Pidd1-/- cells.