Shen Zhang

Shanghai Jiao Tong University

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Qing Zhong

Jilin University

Mindan Tong

Shanghai Jiao Tong University

Xiaoxia Liu

Southern University of Science and Technology

Linsen Li

Xi'an Jiaotong University

Yuehan Wei

Monash University

Yiqing Zhang

Chinese Academy of Sciences

Nilay Nandi

Southwestern Medical Center

Yujun Han

Nanjing University of Chinese Medicine

Liufu Deng

Shanghai Jiao Tong University

Weigang Yuan

Tongji Hospital

Cooperative Institutions

Shanghai Jiao Tong University

The University of Texas Southwestern Medical Center

Shanghai Ninth People's Hospital

Chinese Academy of Sciences

Southwestern Medical Center

Huazhong University of Science and Technology

University of Chinese Academy of Sciences

Nanjing University of Chinese Medicine

Chinese Academy of Medical Sciences & Peking Union Medical College

Renji Hospital

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STING controls energy stress-induced autophagy and energy metabolism via STX17

The Journal of Cell Biology (2022)

Yueguang Rong Shen Zhang Nilay Nandi Zhe Wu Linsen Li

The stimulator of interferon genes (STING) plays a critical role in innate immunity. Emerging evidence suggests that STING is important for DNA or cGAMP-induced non-canonical autophagy, which is independent of a large part of canonical autophagy machineries. Here, we report that, in the absence of STING, energy stress-induced autophagy is upregulated rather than downregulated. Depletion of STING in Drosophila fat cells enhances basal- and starvation-induced autophagic flux. During acute exercise, STING knockout mice show increased autophagy flux, exercise endurance, and altered glucose metabolism. Mechanistically, these observations could be explained by the STING-STX17 interaction. STING physically interacts with STX17, a SNARE that is essential for autophagosome biogenesis and autophagosome-lysosome fusion. Energy crisis and TBK1-mediated phosphorylation both disrupt the STING-STX17 interaction, allow different pools of STX17 to translocate to phagophores and mature autophagosomes, and promote autophagic flux. Taken together, we demonstrate a heretofore unexpected function of STING in energy stress-induced autophagy through spatial regulation of autophagic SNARE STX17.

Sting

10.1083/jcb.202202060

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ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores

Cell Discovery (2024)

Bin Wei Yuhui Fu Xiuzhi Li Chen Fang Yiqing Zhang

Abstract Macroautophagy is a process that cells engulf cytosolic materials by autophagosomes and deliver them to lysosomes for degradation. The biogenesis of autophagosomes requires ATG2 as a lipid transfer protein to transport lipids from existing membranes to phagophores. It is generally believed that endoplasmic reticulum is the main source for lipid supply of the forming autophagosomes; whether ATG2 can transfer lipids from other organelles to phagophores remains elusive. In this study, we identified a new ATG2A-binding protein, ANKFY1. Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux, which largely phenocopied ATG2A/B depletion. A pool of ANKFY1 co-localized with ATG2A between endosomes and phagophores and depletion of UVRAG, ANKFY1 or ATG2A/B led to reduction of PI3P distribution on phagophores. Purified recombinant ANKFY1 bound to PI3P on membrane through its FYVE domain and enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes. Therefore, we propose that ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. This finding implicates a new lipid source for ATG2A-mediated phagophore expansion, where endosomes donate PI3P and other lipids to phagophores via lipid transfer.

10.1038/s41421-024-00659-y

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Human YKT6 forms priming complex with STX17 and SNAP29 to facilitate autophagosome-lysosome fusion

Cell Reports (2024)

Denghao Zheng Mindan Tong Shen Zhang Yi Pan Yanxiang Zhao

Autophagy is crucial for degrading and recycling cellular components. Fusion between autophagosomes and lysosomes is pivotal, directing autophagic cargo to degradation. This process is driven by STX17-SNAP29-VAMP8 and STX7-SNAP29-YKT6 in mammalian cells. However, the interaction between STX17 and YKT6 and its significance remain to be revealed. In this study, we challenge the notion that STX17 and YKT6 function independently in autophagosome-lysosome fusion. YKT6, through its SNARE domain, forms a complex with STX17 and SNAP29 on autophagosomes, enhancing autophagy flux. VAMP8 displaces YKT6 from this complex, leading to the formation of the fusogenic complex STX17-SNAP29-VAMP8. We demonstrated that the YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by STX17-SNAP29-VAMP8, suggesting a priming role of YKT6 for efficient membrane fusion. Our results provide a potential regulation mechanism of autophagosome-lysosome fusion, highlighting the importance of YKT6 and its interactions with STX17 and SNAP29 in promoting autophagy flux.

Priming (agriculture)

Autophagosome

10.1016/j.celrep.2024.113760

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Persistent activation of TRPM4 triggers necrotic cell death characterized by sodium overload

Nature Chemical Biology (2025)

Wan Fu Jianghuang Wang Tianyu Li Yuhui Qiao Zili Zhang

10.1038/s41589-025-01841-3

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