Inhibition of clathrin-mediated endocytosis by knockdown of AP-2 leads to alterations in the plasma membrane proteome

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2021
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Tobys, David
Kowalski, Lisa Maria
Cziudaj, Eva
Müller, Stefan
Zentis, Peter
Pach, Elke
Zigrino, Paola
Höning, Stefan
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Traffic. Wiley-Blackwell. 2021, 22(1-2), pp. 6-22. ISSN 1398-9219. eISSN 1600-0854. Available under: doi: 10.1111/tra.12770
Zusammenfassung

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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ISO 690TOBYS, David, Lisa Maria KOWALSKI, Eva CZIUDAJ, Stefan MÜLLER, Peter ZENTIS, Elke PACH, Paola ZIGRINO, Tobias BLÄSKE, Stefan HÖNING, 2021. Inhibition of clathrin-mediated endocytosis by knockdown of AP-2 leads to alterations in the plasma membrane proteome. In: Traffic. Wiley-Blackwell. 2021, 22(1-2), pp. 6-22. ISSN 1398-9219. eISSN 1600-0854. Available under: doi: 10.1111/tra.12770
BibTex
@article{Tobys2021-01Inhib-52302,
  year={2021},
  doi={10.1111/tra.12770},
  title={Inhibition of clathrin-mediated endocytosis by knockdown of AP-2 leads to alterations in the plasma membrane proteome},
  number={1-2},
  volume={22},
  issn={1398-9219},
  journal={Traffic},
  pages={6--22},
  author={Tobys, David and Kowalski, Lisa Maria and Cziudaj, Eva and Müller, Stefan and Zentis, Peter and Pach, Elke and Zigrino, Paola and Bläske, Tobias and Höning, Stefan}
}
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