TY - JOUR
T1 - PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment
AU - Missiroli, Sonia
AU - Perrone, Mariasole
AU - Gafà, Roberta
AU - Nicoli, Francesco
AU - Bonora, Massimo
AU - Morciano, Giampaolo
AU - Boncompagni, Caterina
AU - Marchi, Saverio
AU - Lebiedzinska-Arciszewska, Magdalena
AU - Vezzani, Bianca
AU - Lanza, Giovanni
AU - Kricek, Franz
AU - Borghi, Alessandro
AU - Fiorica, Francesco
AU - Ito, Keisuke
AU - Wieckowski, Mariusz R.
AU - Di Virgilio, Francesco
AU - Abelli, Luigi
AU - Pinton, Paolo
AU - Giorgi, Carlotta
N1 - Funding Information:
The Signal Transduction Laboratory is supported by the Italian Association for Cancer Research (IG-23670 to PP, IG-19803 to CG and IG 22883 to FDV), A-ROSE, Progetti di Rilevante Interesse Nazionale (PRIN2017E5L5P3 to PP and PRIN20177E9EPY to CG), the Italian Ministry of Health (GR-2019-12369646 to SM), the European Research Council (853057-InflaPML to CG) and local funds from the University of Ferrara to CG and PP. MRW was supported by the National Science Centre, Poland (UMO-2018/29/B/NZ1/00589). MLA was funded by a Polish National Science Centre grant (UMO-2015/17/D/NZ1/00030). MP is supported by an AIRC research fellowship (ID: 26665).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2023/2
Y1 - 2023/2
N2 - Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.
AB - Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.
UR - http://www.scopus.com/inward/record.url?scp=85143162017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85143162017&partnerID=8YFLogxK
U2 - 10.1038/s41418-022-01095-9
DO - 10.1038/s41418-022-01095-9
M3 - Article
C2 - 36450825
AN - SCOPUS:85143162017
SN - 1350-9047
VL - 30
SP - 429
EP - 441
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 2
ER -
