CD147 promotes NSCLC metastasis by inducing secretory autophagy-dependent exosome secretion via TRIM56-mediated ubiquitination and degradation of GCN2

作者：Jie Yang, Cheng‐Gong Liao, Xiaohua Liang, Ke Yuan, Ying Sun, Minmin Huang, Meirui Qian, Xu Yang, Hong‐Yong Cui, Huijie Bian, Zhi‐Nan Chen, Ling‐Min Kong · 发表于：Cell Death and Differentiation · 年份：2025 · DOI：10.1038/s41418-025-01636-y · 被引用次数：1 · 研究领域：Extracellular vesicles in disease、Signaling Pathways in Disease、Autophagy in Disease and Therapy

Tumor-derived exosome secretion dynamically correlates with malignant progression, although the mechanisms by which tumor-associated antigens regulate exosome production remain unclear. Here, we found that the number of plasma exosomes increased significantly with the progression of non-small-cell lung cancer (NSCLC) patients and identified that CD147 as a crucial mediator of exosome secretion using mass spectrometry. CD147 exhibited a positive correlation with exosomes release in NSCLC patients and various cell lines and it drove the release of exosome to promote tumor metastasis in vitro and in vivo. Transcriptomic profiling of transgenic CD147 models identified differential gene expression patterns enriched in autophagy-related pathways. Intriguingly, CD147 was found to specifically enhance autophagosome and amphisome biogenesis to promote exosomes release by using transmission electron microscopy, high-sensitivity structured light microscope, RFP-GFP-LC3 adenovirus reporters and immunofluorescence, which indicated the role of CD147 in mediating non-canonical autophagy processes. Mechanistically, CD147 activated the GCN2/EIF2α/ATG12 signaling axis to drive autophagosome assembly but blocked autolysosome maturation by inhibiting VAMP8/STX17/SNAP29-dependent fusion, leading to amphisome accumulation. Proteomics identified TRIM56 as a novel E3 ligase mediating K619 ubiquitination-dependent GCN2 proteasomal degradation. Subsequently, we found that CD147 suppresses TRIM56 expre...