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

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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.

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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.

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Eszter Zavodszky

Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4123-8758
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.

"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.

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