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

• Published in: Nature communications Vol. 16; no. 1; pp. 5826 - 22
• Main Authors: Zhang, Rui, Zhang, Xin, Bai, Hua, Cheng, Qiuyu, Yao, Xia, Li, Shi, Torraca, Vincenzo, Yan, Chaojun, Dong, Xueying, Miao, Siyi, Hu, Xueyuan, Yu, Yeping, Wu, Yueyan, Tan, Hongfei, Chen, Xin, Liu, Shicheng, Lyu, Hao, Xiao, Shuai, Guo, Dong, Zhang, Qi, Chen, Xing-Zhen, Song, Zhiyin, Zhou, Cefan, Tang, Jingfeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 59/5; 631/67/2195; 631/80/39/2346; 631/80/458; 64/116; 64/60; Animal models; Animals; Autophagosomes - metabolism; Autophagy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Damage; Degradation; Deoxyribonucleic acid; DNA; DNA damage; Energy balance; Experiments; Extravasation; HEK293 Cells; Hepatocellular carcinoma; Homeostasis; Humanities and Social Sciences; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lymphocytes; Lysosomes; Lysosomes - metabolism; Membrane Fusion; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Metastasis; multidisciplinary; Phagosomes; Protein Binding; Protein Stability; Proteins; Qa-SNARE Proteins - metabolism; Qb-SNARE Proteins - metabolism; Qc-SNARE Proteins - metabolism; R-SNARE Proteins - genetics; R-SNARE Proteins - metabolism; Science; Science (multidisciplinary); Stability; Ubiquitination; Xenotransplantation; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-60887-y

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. DNA Damage Regulated Autophagy Modulator 1 (DRAM1) plays pivotal roles in autophagy regulation. Here, the authors show that DRAM1 stabilizes lysosomal VAMP8, thereby promoting autolysosome maturation. Furthermore, they establish that DRAM1–VAMP8 axis enhances autophagic flux and facilitates hepatocellular carcinoma extravasation, as validated in both zebrafish xenograft and mouse metastatic models.