Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
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.
Nat Commun. 2023 Sep 28;14(1):6069. doi: 10.1038/s41467-023-41739-z.
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.
PI3K/AKT 通路在肿瘤发生发展中起着至关重要的作用。NOD 样受体（NLRs）调节先天免疫，与癌症有关，但它们是否参与 PI3K/AKT 通路的调节尚不清楚。在这里，我们报告 NLRP6 通过与 PI3K 的调节亚基 p85α 结合并使其不稳定来增强 PI3K/AKT 通路。在机制上，NLRP6 将 E3 连接酶 RBX1 募集到 p85α 上，并使 p85α 上的赖氨酸 256 发生泛素化，这被自噬货物受体 OPTN 识别，导致 p85α 的选择性自噬降解，并通过降低 PTEN 的稳定性来激活 PI3K/AKT 通路。我们进一步表明，NLRP6 的缺失抑制了体外和体内神经胶质瘤细胞的增殖、集落形成、细胞迁移和肿瘤生长。使用 Pep9 肽破坏 NLRP6/p85α 相互作用会抑制 PI3K/AKT 通路并产生强大的抗肿瘤作用。总之，我们的研究结果表明，NLRP6 通过选择性自噬促进 p85α 的降解以驱动肿瘤发生，并且 NLRP6 和 p85α 之间的相互作用可以成为肿瘤治疗的有前途的治疗靶点。
