Xiao Juan, Zhang Tao, Xu Daichao, Wang Huibing, Cai Yu, Jin Taijie, Liu Min, Jin Mingzhi, Wu Kejia, Yuan Junying
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2015 Jan 15;29(2):184-96. doi: 10.1101/gad.252528.114.
Vacuolar protein-sorting 34 (Vps34), the catalytic subunit in the class III PtdIns3 (phosphatidylinositol 3) kinase complexes, mediates the production of PtdIns3P, a key intracellular lipid involved in regulating autophagy and receptor degradation. However, the signal transduction pathways by which extracellular signals regulate Vps34 complexes and the downstream cellular mechanisms are not well understood. Here we show that DNA damage-activated mitotic arrest and CDK activation lead to the phosphorylation of Vps34, which provides a signal to promote its ubiquitination and proteasomal degradation mediated by FBXL20 (an F-box protein) and the associated Skp1 (S-phase kinase-associated protein-1)-Cullin1 complex, leading to inhibition of autophagy and receptor endocytosis. Furthermore, we show that the expression of FBXL20 is regulated by p53-dependent transcription. Our study provides a molecular pathway by which DNA damage regulates Vps34 complexes and its downstream mechanisms, including autophagy and receptor endocytosis, through SCF (Skp1-Cul1-F-box)-mediated ubiquitination and degradation. Since the expression of FBXL20 is regulated by p53-dependent transcription, the control of Vps34 ubiquitination and proteasomal degradation by FBXL20 and the associated SCF complex expression provides a novel checkpoint for p53 to regulate autophagy and receptor degradation in DNA damage response.
液泡蛋白分选蛋白34（Vps34）是III类磷脂酰肌醇3（PtdIns3）激酶复合物中的催化亚基，介导PtdIns3P的产生，PtdIns3P是一种参与调节自噬和受体降解的关键细胞内脂质。然而，细胞外信号调节Vps34复合物的信号转导途径及其下游细胞机制尚不清楚。在此，我们表明DNA损伤激活的有丝分裂停滞和CDK激活导致Vps34磷酸化，这提供了一个信号来促进其由FBXL20（一种F盒蛋白）和相关的Skp1（S期激酶相关蛋白1）-Cullin1复合物介导的泛素化和蛋白酶体降解，从而导致自噬和受体内吞作用受到抑制。此外，我们表明FBXL20的表达受p53依赖性转录调控。我们的研究提供了一条分子途径，通过该途径DNA损伤通过SCF（Skp1-Cul1-F盒）介导的泛素化和降解来调节Vps34复合物及其下游机制，包括自噬和受体内吞作用。由于FBXL20的表达受p53依赖性转录调控，FBXL20对Vps34泛素化和蛋白酶体降解的控制以及相关SCF复合物的表达为p53在DNA损伤反应中调节自噬和受体降解提供了一个新的检查点。
