Misfolded GPI-anchored proteins are escorted through the secretory pathway by ER-derived factors

  1. Eszter Zavodszky
  2. Ramanujan S Hegde  Is a corresponding author
  1. MRC Laboratory of Molecular Biology, United Kingdom

Abstract

We have used misfolded prion protein (PrP*) as a model to investigate how mammalian cells recognize and degrade misfolded GPI-anchored proteins. While most misfolded membrane proteins are degraded by proteasomes, misfolded GPI-anchored proteins are primarily degraded in lysosomes. Quantitative flow cytometry analysis showed that at least 85% of PrP* molecules transiently access the plasma membrane en route to lysosomes. Unexpectedly, time-resolved quantitative proteomics revealed a remarkably invariant PrP* interactome during its trafficking from the ER to lysosomes. Hence, PrP* arrives at the plasma membrane in complex with ER-derived chaperones and cargo receptors. These interaction partners were critical for rapid endocytosis because a GPI-anchored protein induced to misfold at the cell surface was not recognized effectively for degradation. Thus, resident ER factors have post-ER itineraries that not only shield misfolded GPI-anchored proteins during their trafficking, but also provide a quality control cue at the cell surface for endocytic routing to lysosomes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data for Fig. 5E has been provided as a figure supplement.

Article and author information

Author details

  1. Eszter Zavodszky

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4123-8758
  2. Ramanujan S Hegde

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    rhegde@mrc-lmb.cam.ac.uk
    Competing interests
    Ramanujan S Hegde, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8338-852X

Funding

Medical Research Council (MC_UP_A022_1007)

  • Ramanujan S Hegde

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maya Schuldiner, Weizmann Institute, Israel

Publication history

  1. Received: March 11, 2019
  2. Accepted: May 15, 2019
  3. Accepted Manuscript published: May 16, 2019 (version 1)
  4. Version of Record published: May 29, 2019 (version 2)

Copyright

© 2019, Zavodszky & Hegde

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Eszter Zavodszky
  2. Ramanujan S Hegde
(2019)
Misfolded GPI-anchored proteins are escorted through the secretory pathway by ER-derived factors
eLife 8:e46740.
https://doi.org/10.7554/eLife.46740

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