期刊
TRAFFIC
卷 22, 期 1-2, 页码 6-22出版社
WILEY
DOI: 10.1111/tra.12770
关键词
ADAM10; Alzheimer; BACE1; blood‐ brain‐ barrier; endosome; lysosome; receptor internalization; surface proteomics; surfaceome; transcytosis
类别
资金
- Cologne Fortune Program of the Medical Faculty
- Deutsche Forschungsgemeinschaft [73111208, SFB829]
Inhibiting clathrin-mediated endocytosis (CME) by depleting AP-2 led to the accumulation of major constituents of the endosomal-lysosomal system, enrichment of integrins, and severely impaired cell migration. Additionally, rare proteins such as anti-cancer drug target CA9 and tumor markers were significantly enriched, indicating that blocking AP-2 function may help identify new druggable targets.
In eukaryotic cells, clathrin-mediated endocytosis (CME) is a central pathway for the internalization of proteins from the cell surface, thereby contributing to the maintenance of the plasma membrane protein composition. A key component for the formation of endocytic clathrin-coated vesicles (CCVs) is AP-2, as it sequesters cargo membrane proteins, recruits a multitude of other endocytic factors and initiates clathrin polymerization. Here, we inhibited CME by depletion of AP-2 and explored the consequences for the plasma membrane proteome. Quantitative analysis revealed accumulation of major constituents of the endosomal-lysosomal system reflecting a block in retrieval by compensatory CME. The noticeable enrichment of integrins and blockage of their turnover resulted in severely impaired cell migration. Rare proteins such as the anti-cancer drug target CA9 and tumor markers (CD73, CD164, CD302) were significantly enriched. The AP-2 knockdown attenuated the global endocytic capacity, but clathrin-independent entry pathways were still operating, as indicated by persistent internalization of specific membrane-spanning and GPI-anchored receptors (PVR, IGF1R, CD55, TNAP). We hypothesize that blocking AP-2 function and thus inhibiting CME may be a novel approach to identify new druggable targets, or to increase their residence time at the plasma membrane, thereby increasing the probability for efficient therapeutic intervention.
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