2. Academic Validation
  3. DRAM1 promotes the stability of lysosomal VAMP8 to enhance autolysosome formation and facilitates the extravasation

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

  • Nat Commun. 2025 Jul 1;16(1):5826. doi: 10.1038/s41467-025-60887-y.
Rui Zhang # 1,  Xin Zhang # 1,  Hua Bai # 1,  Qiuyu Cheng 1,  Xia Yao 1,  Shi Li 1,  Vincenzo Torraca 2,  Chaojun Yan 1,  Xueying Dong 1,  Siyi Miao 1,  Xueyuan Hu 1,  Yeping Yu 1,  Yueyan Wu 1,  Hongfei Tan 1,  Xin Chen 1,  Shicheng Liu 1,  Hao Lyu 1,  Shuai Xiao 1,  Dong Guo 1,  Qi Zhang 1,  Xing-Zhen Chen 3,  Zhiyin Song 4,  Cefan Zhou 5,  Jingfeng Tang 6
Affiliations

Affiliations

  • 1 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China.
  • 2 Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK.
  • 3 Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
  • 4 Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. songzy@hust.edu.cn.
  • 5 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China. cefan@hbut.edu.cn.
  • 6 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China. Jingfeng_hut@163.com.
  • # Contributed equally.
PMID: 40595569 DOI: 10.1038/s41467-025-60887-y
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.

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