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New frontiers in quality control: the case of GPI-anchored proteins

Nature Reviews Molecular Cell Biology volume 24, pages 599–600 (2023)Cite this article

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The biosynthesis and trafficking of glycosylphosphatidylinositol-anchored proteins (GPI-APs), many of enormous clinical importance, are complex multistep processes involving dozens of dedicated factors. Recent work indicates that the quality control of GPI-APs is similarly complex, varying substantially between different eukaryotic species and relying on several previously unknown cellular mechanisms.

Protein quality control (QC) is fundamental for monitoring the folding, assembly and processing of newly synthesized polypeptides. In the secretory pathway of the eukaryotic cell, protein folding starts at the endoplasmic reticulum (ER) as unfolded polypeptides are translocated across or integrated into the ER membrane. QC inside the ER permits the selective export of proteins that fold successfully while terminally misfolded species are retained and eventually routed for degradation. The most widely studied degradation pathway, ER-associated degradation (ERAD), involves substrate retrotranslocation into the cytosol for degradation by the proteasome. Although ERAD is thought to oversee the QC of most secretory and membrane proteins, recent work has shown that the QC of GPI-APs is often uncoupled from ERAD and instead relies on distinct cellular pathways that vary across different eukaryotic species (see Supplementary Fig. 1 for a display of mechanisms related to the QC of GPI-APs).

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Acknowledgements

L.L. and V.G. are supported by Agencia Estatal de Investigación (PID2019-108564GB-I00 and MCIN/AEI/10.13039/501100011033). L.L. is a fellow of the European Regional Development Fund from the Junta de Andalucía. R.S.H. is supported by the Medical Research Council, part of UK Research and Innovation (grant number MC_UP_A022_1007).

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Authors and Affiliations

  1. Department of Genetics, University of Seville, Seville, Spain

    Leticia Lemus & Veit Goder

  2. Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, UK

    Ramanujan S. Hegde

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  1. Leticia Lemus
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  2. Ramanujan S. Hegde
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Correspondence to Leticia Lemus or Veit Goder.

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Nature Reviews Molecular Cell Biology thanks the anonymous, reviewer(s) for their contribution to the peer review of this work.

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Lemus, L., Hegde, R.S. & Goder, V. New frontiers in quality control: the case of GPI-anchored proteins. Nat Rev Mol Cell Biol 24, 599–600 (2023). https://doi.org/10.1038/s41580-023-00616-9

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