2. Academic Validation
  3. S-palmitoylation modulates ATG2-dependent non-vesicular lipid transport during starvation-induced autophagy

S-palmitoylation modulates ATG2-dependent non-vesicular lipid transport during starvation-induced autophagy

  • EMBO J. 2025 May;44(9):2596-2619. doi: 10.1038/s44318-025-00410-7.
Wenhui Zheng # 1,  Maomao Pu # 1,  Sai Zeng 1,  Hongtao Zhang 1,  Qian Wang 1,  Tao Chen 1,  Tianhua Zhou 1,  Chunmei Chang 2,  Dante Neculai 3,  Wei Liu 4 5
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 2 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. chunmei_chang@fudan.edu.cn.
  • 3 Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. dneculai@zju.edu.cn.
  • 4 Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. liuwei666@zju.edu.cn.
  • 5 Department of Ultrasound Medicine and State Key laboratory Implantation Device, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China. liuwei666@zju.edu.cn.
  • # Contributed equally.
PMID: 40128367 DOI: 10.1038/s44318-025-00410-7
Abstract

Lipid transfer proteins mediate the non-vesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Despite significant recent advances in our understanding of the structural basis for lipid transfer, its functional regulation remains unclear. In this study, we report that S-palmitoylation modulates the cellular function of ATG2, a rod-like lipid transfer protein responsible for transporting Phospholipids from the endoplasmic reticulum (ER) to phagophores during autophagosome formation. During starvation-induced Autophagy, ATG2A undergoes depalmitoylation as the balance between ZDHHC11-mediated palmitoylation and APT1-mediated depalmitoylation. Inhibition of ATG2A depalmitoylation leads to impaired autophagosome formation and disrupted autophagic flux. Further, in cell and in vitro analyses demonstrate that S-palmitoylation at the C-terminus of ATG2A anchors the C-terminus to the ER. Depalmitoylation detaches the C-terminus from the ER membrane, enabling it to interact with phagophores and promoting their growth. These findings elucidate a S-palmitoylation-dependent regulatory mechanism of cellular ATG2, which may represent a broad regulatory strategy for lipid transport mediated by bridge-like transporters within cells.

Keywords

ATG2; Autophagy; Lipid Transfer Protein; S-palmitoylation.

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