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.