Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance

Unscheduled increases in ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of centrosomes, the main microtubule organization centers in animal cells. Supernumerary centrosomes are frequent in tumors, correlating with higher aggressiveness and poor prognosis. However, extra centrosomes initially also exert an onco-protective effect by activating p53-induced cell cycle arrest. If additional signaling events initiated by centrosomes help prevent pathology is unknown. 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 increase the immunogenicity of cancer cells and render them more susceptible to NK-cell attack. Hence, 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.

非计划性倍体升高是组织功能障碍、早衰及恶性肿瘤发生的基础诱因。多倍体化过程伴随的一项事件为中心体（centrosomes）的扩增——中心体是动物细胞内主要的微管组织中心。肿瘤组织中常可见额外中心体，且与肿瘤更高的侵袭性及不良预后相关。但额外中心体最初亦可通过激活p53介导的细胞周期阻滞发挥抗肿瘤保护作用。目前尚不清楚由中心体启动的额外信号事件是否有助于抑制病理进程。本研究表明，在非计划性多倍体化过程中产生的额外中心体，或异常中心粒发生过程中形成的额外中心体，可诱导核因子κB（NF-κB）信号通路激活及无菌性炎症发生。该信号通路依赖于由PIDD1、RIPK1及NEMO/IKKγ构成的多蛋白复合体NEMO-PIDDosome。值得注意的是，仅额外中心体的存在即可诱导产生旁分泌趋化因子与细胞因子谱，进而将巨噬细胞极化为促炎表型。此外，额外中心体可增强癌细胞的免疫原性，使其更易受到自然杀伤（NK）细胞的攻击。综上，NEMO-PIDDosome发挥双重效应功能：既可参与p53网络以调控细胞周期，又可通过激活NF-κB信号通路指导固有免疫应答。