Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, China.
Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, China.
FASEB J. 2019 Apr;33(4):5535-5547. doi: 10.1096/fj.201801987R. Epub 2019 Jan 16.
Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in regulating cell survival, cell growth, and proliferation by antagonizing the PI3K-AKT-mTOR pathway. The regulatory mechanism of PTEN protein is still not completely understood. Here, we found that Sirtuin 4 (SIRT4) interacts with PTEN and regulates its stability. Overexpression of SIRT4 in cells causes down-regulation of PTEN. This regulation is independent of PTEN acetylation and ubiquitination. We further found that SIRT4 degrades PTEN through lysosome pathway mediated by insulin degrading enzyme (IDE). SIRT4 bridges PTEN and IDE for degradation in response to nutritional starvation stresses. Our results suggest that when cells were exposed to nutritional starvation, SIRT4 was induced and cooperated with IDE to degrade PTEN; low levels of PTEN promote cells to survive from cellular stress. Our findings provide a new regulation of PTEN in response to cellular stresses.-Liu, M., Wang, Z., Ren, M., Yang, X., Liu, B., Qi, H., Yu, M., Song, S., Chen, S., Liu, L., Zhang, Y., Zou, J., Zhu, W.-G., Yin, Y., Luo, J. SIRT4 regulates PTEN stability through IDE in response to cellular stresses.
抑癌基因磷酸酶和张力蛋白同源物缺失于第 10 号染色体（PTEN）通过拮抗 PI3K-AKT-mTOR 通路在调节细胞存活、细胞生长和增殖方面发挥着关键作用。PTEN 蛋白的调节机制尚不完全清楚。在这里，我们发现 Sirtuin 4（SIRT4）与 PTEN 相互作用并调节其稳定性。细胞中 SIRT4 的过表达导致 PTEN 的下调。这种调节不依赖于 PTEN 的乙酰化和泛素化。我们进一步发现 SIRT4 通过胰岛素降解酶（IDE）介导的溶酶体途径降解 PTEN。SIRT4 通过响应营养饥饿应激将 PTEN 和 IDE 桥接起来进行降解。我们的结果表明，当细胞暴露于营养饥饿时，SIRT4 被诱导并与 IDE 合作降解 PTEN；PTEN 水平降低可促进细胞从细胞应激中存活。我们的发现为细胞应激时 PTEN 的调节提供了新的认识。-刘，M.，王，Z.，任，M.，杨，X.，刘，B.，齐，H.，于，M.，宋，S.，陈，S.，刘，L.，张，Y.，邹，J.，朱，W.-G.，尹，Y.，罗，J. SIRT4 通过 IDE 在细胞应激下调节 PTEN 稳定性。
