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.

Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance / Garcia-Carpio, Irmina; Braun, Vincent Z; Weiler, Elias S; Leone, Marina; Niñerola, Sergio; Barco, Angel; Fava, Luca; Villunger, Andreas. - In: EMBO JOURNAL. - ISSN 1460-2075. - 42:20(2023), pp. e11351001-e11351022. [10.15252/embj.2023113510]

Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance

Fava, Luca;
2023-01-01

Abstract

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.
2023
20
Garcia-Carpio, Irmina; Braun, Vincent Z; Weiler, Elias S; Leone, Marina; Niñerola, Sergio; Barco, Angel; Fava, Luca; Villunger, Andreas...espandi
Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance / Garcia-Carpio, Irmina; Braun, Vincent Z; Weiler, Elias S; Leone, Marina; Niñerola, Sergio; Barco, Angel; Fava, Luca; Villunger, Andreas. - In: EMBO JOURNAL. - ISSN 1460-2075. - 42:20(2023), pp. e11351001-e11351022. [10.15252/embj.2023113510]
File in questo prodotto:
File Dimensione Formato  
garcia.pdf

accesso aperto

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Creative commons
Dimensione 4.58 MB
Formato Adobe PDF
4.58 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/402197
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 6
social impact