2. Academic Validation
  3. NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis

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

  • Nat Commun. 2023 Sep 28;14(1):6069. doi: 10.1038/s41467-023-41739-z.
Feng Zhi # 1,  Bowen Li # 1,  Chuanxia Zhang # 2 3,  Fan Xia # 2,  Rong Wang 1,  Weihong Xie 2,  Sihui Cai 2,  Dawei Zhang 4,  Ren Kong 4,  Yiqiao Hu 5,  Yilin Yang 1,  Ya Peng 6,  Jun Cui 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
  • 2 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 3 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
  • 4 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Medical School and School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
  • 6 Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China. [email protected].
  • 7 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 37770465 DOI: 10.1038/s41467-023-41739-z
Abstract

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 p85α, the regulatory subunit of PI3K. Mechanistically, NLRP6 recruits the E3 ligase RBX1 to p85α and ubiquitinates lysine 256 on p85α, which is recognized by the Autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α 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/p85α interaction using the Pep9 peptide inhibits the PI3K/Akt pathway and generates potent antitumour effects. Collectively, our results suggest that NLRP6 promotes p85α degradation via selective Autophagy to drive tumorigenesis, and the interaction between NLRP6 and p85α can be a promising therapeutic target for tumour treatment.

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