Lysosomal TMEM165 remodels calcium signaling to drive hypoxia adaptation and tumor progression
Abstract
Hypoxia is a common stress encountered by animal tissues during development, physiology, and disease. To cope with hypoxic stress, cells remodel metabolic and signaling networks to preserve viability and function. Lysosomes serve as central hubs for metabolic control and intracellular signaling, yet their role in hypoxic adaptation remains unclear. Here, we identify the lysosomal calcium transporter TMEM165 as a hypoxia-responsive regulator of cellular homeostasis. Under hypoxic conditions, TMEM165 expression increases, promoting calcium redistribution from the endoplasmic reticulum to lysosomes and expanding lysosomal calcium storage capacity. TMEM165 activation regulates autophagy and senescence through the AMPK-mTOR and ERK/p21 signaling pathways, respectively. In glioma, high TMEM165 expression correlates with poor prognosis, whereas its depletion suppresses glycolysis, proliferation, and tumor progression. These findings establish TMEM165 as a lysosomal hypoxia-responsive protein that integrates calcium signaling with metabolic and stress-response pathways, revealing a mechanistic link between oxygen availability, lysosomal function, and tumor adaptation.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Yu Zeng
Meiting Chen
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Yu Cao
Stanford University , , , ,
Yan Huang
Xingguo Yang
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Qian Jiang
State Key Laboratory of Loess Science, Institute of Earth Environment, Chinese Academy of Sciences
Jiamin Huang
The Center for Photochemical Sciences
Yu Chen
Xin Du
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Wenping Zeng
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Qiankun Mao
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Huafeng Zhang
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Li Wang
The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China
Xiaomei Li
Canjun Li
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Lili Qu
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Chunlei Cang
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China