A CHKA–PML autophagy checkpoint enables tumors to evade glutamine starvation
Abstract
Glutamine metabolism is essential for tumor cell proliferation and biosynthesis. However, solid tumors often face chronic glutamine deprivation, and the underlying adaptive mechanisms remain incompletely understood. Here, we show that glutamine scarcity upregulates choline kinase alpha (CHKA), whose monomerization enhances its noncanonical protein kinase activity. CHKA phosphorylates promyelocytic leukemia (PML) at tyrosine 339, promoting its cytoplasmic localization. Notably, this reflects a compartment-specific switch in PML activity: while nuclear PML facilitates protein degradation through Small Ubiquitin-like Modifier (SUMO)-ubiquitin cascades, cytoplasmic PML acts oppositely to block degradation. Specifically, cytoplasmic PML then induces SUMOylation of WD Repeat Domain Phosphoinositide-Interacting Protein 2 (WIPI2) at lysines 281 and 283, thereby blocking HUWE1-mediated ubiquitination and proteasomal degradation. Stabilized WIPI2 increases autophagic flux, supporting tumor cell survival under metabolic stress. This study identifies a critical CHKA–PML–WIPI2 axis mediating adaptation to glutamine deprivation, providing insight into metabolic plasticity and a potential therapeutic target for glutamine-dependent cancers.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Ruijie Wang
National Synchrotron Radiation Laboratory, State Key Laboratory of Precision and Intelligent Chemistry, School of Nuclear Science and Technology
Leixi Cao
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University
Xianwei He
School of Clinical Medicine, Henan University
Rick Francis Thorne
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University
Qichen Wu
School of Clinical Medicine, Henan University
Caoyuan Ding
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University
Jinjing Zhang
School of Clinical Medicine, Henan University
Mengfan Li
State Key Laboratory of Chemical Biology & Center of Pharmaceutics
Zeyuan Shi
The Department of Pathology, The First Affiliated Hospital of Zhengzhou University
Xinyi Dong
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University
Jing Li
Hongxiang Li
College of Polymer Science and Engineering State Key Laboratory of Polymer Materials Engineering
Suhua Gao
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University
Jinming Li
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University
Xu Dong Zhang
School of Biomedical Sciences and Pharmacy, The University of Newcastle
Lei Jin
Tianli Fan
Department of Pharmacology, School of Basic Medicine, Zhengzhou University
Mian Wu
Translational Research Institute of People’s Hospital of Zhengzhou University, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University