Ago2/CAV1 interaction potentiates metastasis via controlling Ago2 localization and miRNA action

• Published in: EMBO reports 2024-05, Vol.25 (5), p.2441-2478
• Main Authors: Lin, Meng-Chieh, Kuo, Wen-Hung, Chen, Shih-Yin, Hsu, Jing-Ya, Lu, Li-Yu, Wang, Chen-Chi, Chen, Yi-Ju, Tsai, Jia-Shiuan, Li, Hua-Jung
• Format: Article
• Language: English
• Subjects: Animals; Argonaute Proteins - genetics; Argonaute Proteins - metabolism; Biomedical and Life Sciences; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cell Line, Tumor; EMBO03; EMBO36; Extracellular Vesicles - metabolism; Gene Expression Regulation, Neoplastic; Humans; Life Sciences; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Protein Binding; Sirtuin 2 - genetics; Sirtuin 2 - metabolism
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00132-7

Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer. Synopsis A direct interaction between Ago2 and CAV1, mediated by the positive charge of Ago2 K212, increases the complexity of miRNA actions and modulates exosomal cargo sorting of metastatic tumors. Ago2 directly binds to the CSD of CAV1 through W199FGFHQSVRPSLWK212, the CBM of Ago2 in cancer cells. The positive charge of Ago2 lysine 212, which is preserved by SIRT-2-mediated deacetylation in cancer cells, in the CBM is required for Ago2/CAV1 interaction. Elevated Ago2/CAV1 interaction in metastatic tumors increases the plasma membrane-association of Ago2, complexity of miRNA-mediated mRNA expression, and Ago2/miRNA release via exosomes. A direct interaction between Ago2 and CAV1, mediated by the positive charge of Ago2 K212, increases the complexity of miRNA actions and modulates exosomal cargo sorting of metastatic tumors.