P62/SQSTM1 mediates the autophagy-lysosome degradation of CDK2 protein undergoing PI3Kα/AKT T308 inhibition.
P62/SQSTM1 mediates the autophagy-lysosome degradation of CDK2 protein undergoing PI3Kα/AKT T308 inhibition.
复制标题
DOI：
10.1016/j.bbrc.2022.08.034
复制
发表时间：
2022-08
影响因子：
3.1
通讯作者：
Chao Zhang;Hong-Liang Zhang;Shangyun Liu;Jun-mei Yang;Feng-Hou Gao
中科院分区：
文献类型：
--
作者：
Chao Zhang;Hong-Liang Zhang;Shangyun Liu;Jun-mei Yang;Feng-Hou Gao
CDK 2与cyclin A和cyclin E形成复合物以促进细胞周期的进展，但当cyclin A和cyclin E从复合物中解离并被泛素蛋白酶体途径降解时，失活的CDK 2的命运尚不清楚。在本研究中，我们发现失活的CDK 2蛋白通过自噬-溶酶体途径被降解。在经典的血清饥饿诱导G 0/G1期阻滞模型中，我们发现CDK 2的mRNA水平没有变化，但蛋白水平下降。随后，使用PI 3 K和AKT抑制剂和基因敲除方法，发现CDK 2降解是通过PI 3 K α/AKTT 308的抑制介导的。此外，发现P62/SQSTM 1与失活的CDK 2蛋白结合，以CTSB依赖性方式帮助其进入自噬-溶酶体降解。综上所述，这些结果证实PI 3 K α/AKTT 308抑制导致自噬-溶酶体途径中CDK 2蛋白的降解。这些数据揭示了CDK 2蛋白降解的新的分子机制，为调控CDK 2蛋白提供了新的策略和方法。
CDK2 forms a complex with cyclin A and cyclin E to promote the progress of cell cycle, but when cyclin A and cyclin E are dissociated from the complex and degraded by the ubiquitin proteasome pathway, the fate of the inactive CDK2 is unclear. In this study, we found that the inactive CDK2 protein was degraded by autophagy-lysosome pathway. In the classic model of G0/G1 phase arrest induced by serum starvation, we found that the mRNA level in CDK2 did not change but the protein level decreased. Subsequently, using PI3K and AKT inhibitors and gene knockout methods, it was found that CDK2 degradation was mediated by the inhibition of PI3Kα/AKTT308. In addition, P62/SQSTM1 was found to bind to the inactivated CDK2 protein to help it enter autophagy-lysosome degradation in a CTSB-dependent manner. Taken together, these results confirm that the PI3Kα/AKTT308inhibition leads to degradation of CDK2 protein in the autophagy-lysosome pathway. These data reveal a new molecular mechanism of CDK2 protein degradation and provide a new strategy and method for regulating CDK2 protein.