NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis

作者：Zhi, Feng; Li, Bowen; Zhang, Chuanxia; Xia, Fan; Wang, Rong; Xie, Weihong; Cai, Sihui; Zhang, Dawei; Kong, Ren; Hu, Yiqiao; Yang, Yilin; Peng, Ya^*; Cui, Jun^*

来源：Nature Communications, 2023, 14(1): 6069.

DOI：10.1038/s41467-023-41739-z

• PROTEIN-PROTEIN
• PTEN
• ACTIVATION
• INFLAMMATION
• INHIBITION
• MECHANISMS
• PEPTIDES

The PI3K/AKT pathway plays an essential role in tumour development. NOD-like receptors (NLRs) regulate innate immunity and are implicated in cancer, but whether they are involved in PI3K/AKT pathway regulation is poorly understood. Here, we report that NLRP6 potentiates the PI3K/AKT pathway by binding and destabilizing p85 alpha, the regulatory subunit of PI3K. Mechanistically, NLRP6 recruits the E3 ligase RBX1 to p85 alpha and ubiquitinates lysine 256 on p85 alpha, which is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85 alpha and subsequent activation of the PI3K/AKT pathway by reducing PTEN stability. We further show that loss of NLRP6 suppresses cell proliferation, colony formation, cell migration, and tumour growth in glioblastoma cells in vitro and in vivo. Disruption of the NLRP6/p85 alpha interaction using the Pep9 peptide inhibits the PI3K/AKT pathway and generates potent antitumour effects. Collectively, our results suggest that NLRP6 promotes p85 alpha degradation via selective autophagy to drive tumorigenesis, and the interaction between NLRP6 and p85 alpha can be a promising therapeutic target for tumour treatment. @@@ The crosstalk between innate immunity and autophagy plays a critical role in cancer. Here, the authors report that an immune receptor NLRP6 potentiates the PI3K/AKT pathway by selective degradation of p85 alpha. The NLRP6-p85 alpha interaction offers a potential therapeutic target for tumor treatment.

• 单位
  南京大学; y; 苏州大学; 江苏大学; 南方医科大学; 广东省人民医院; 中山大学