Author:
Xiao Juan,Zhang Tao,Xu Daichao,Wang Huibing,Cai Yu,Jin Taijie,Liu Min,Jin Mingzhi,Wu Kejia,Yuan Junying
Abstract
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.
Funder
National Institute on Aging
National Institute of Neurological Disorders and Stroke
Global Research Laboratory Program
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
64 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献