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DRAM1 promotes the stability of lysosomal VAMP8 to enhance autolysosome formation and facilitates the extravasation

Author

Listed:
  • Rui Zhang

    (Hubei University of Technology)

  • Xin Zhang

    (Hubei University of Technology)

  • Hua Bai

    (Hubei University of Technology)

  • Qiuyu Cheng

    (Hubei University of Technology)

  • Xia Yao

    (Hubei University of Technology)

  • Shi Li

    (Hubei University of Technology)

  • Vincenzo Torraca

    (King’s College London)

  • Chaojun Yan

    (Hubei University of Technology)

  • Xueying Dong

    (Hubei University of Technology)

  • Siyi Miao

    (Hubei University of Technology)

  • Xueyuan Hu

    (Hubei University of Technology)

  • Yeping Yu

    (Hubei University of Technology)

  • Yueyan Wu

    (Hubei University of Technology)

  • Hongfei Tan

    (Hubei University of Technology)

  • Xin Chen

    (Hubei University of Technology)

  • Shicheng Liu

    (Hubei University of Technology)

  • Hao Lyu

    (Hubei University of Technology)

  • Shuai Xiao

    (Hubei University of Technology)

  • Dong Guo

    (Hubei University of Technology)

  • Qi Zhang

    (Hubei University of Technology)

  • Xing-Zhen Chen

    (University of Alberta)

  • Zhiyin Song

    (Huazhong University of Science and Technology)

  • Cefan Zhou

    (Hubei University of Technology)

  • Jingfeng Tang

    (Hubei University of Technology)

Abstract

Autophagy classically functions to protect cells and organisms during stressful conditions by catabolizing intracellular components to maintain energy homeostasis. Lysosome-autophagosome fusion is a critical step in emptying degraded unwanted contents. However, the mechanism of autophagosome fusion with lysosomes is still not fully understood. Here, we report that DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) interacts with Vesicle Associated Membrane Protein 8 (VAMP8) to mediate the fusion of autophagosomes with lysosomes. This DRAM1-VAMP8 interaction is enhanced upon stimulation of autophagy. However, DRAM1 preferentially mediates the fusion between autophagosomes and lysosomes by enhancing the assembly of the STX17-SNAP29-VAMP8 complex. Moreover, we reveal that DRAM1 specifically promotes the stability of lysosomal VAMP8 via inhibiting VAMP8 degradation by CHIP mediating ubiquitination. We also identify that DRAM1 inhibits the ubiquitination of VAMP8 at Lys 68,72, and 75 via competitively binding with CHIP. Furthermore, we demonstrate that DRAM1 promotes the extravasation of Hepatocellular Carcinoma (HCC) cells, and this process relies on enhanced autophagosome degradation. Our study reveals a mechanism for regulating autolysosome formation by DRAM1-VAMP8 association and suggests a potential strategy to inhibit the extravasation of HCC.

Suggested Citation

  • Rui Zhang & Xin Zhang & Hua Bai & Qiuyu Cheng & Xia Yao & Shi Li & Vincenzo Torraca & Chaojun Yan & Xueying Dong & Siyi Miao & Xueyuan Hu & Yeping Yu & Yueyan Wu & Hongfei Tan & Xin Chen & Shicheng Li, 2025. "DRAM1 promotes the stability of lysosomal VAMP8 to enhance autolysosome formation and facilitates the extravasation," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60887-y
    DOI: 10.1038/s41467-025-60887-y
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    References listed on IDEAS

    as
    1. Hong Huang & Qinqin Ouyang & Min Zhu & Haijia Yu & Kunrong Mei & Rong Liu, 2021. "mTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Hedayatollah Hosseini & Milan M. S. Obradović & Martin Hoffmann & Kathryn L. Harper & Maria Soledad Sosa & Melanie Werner-Klein & Lahiri Kanth Nanduri & Christian Werno & Carolin Ehrl & Matthias Manec, 2016. "Early dissemination seeds metastasis in breast cancer," Nature, Nature, vol. 540(7634), pages 552-558, December.
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