ArticleMolecular biology of the cell2015
A novel UGGT1 and p97-dependent checkpoint for native ectodomains with ionizable intramembrane residue.
Article in Molecular biology of the cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
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- sUPRa is a dual-color reporter for unbiased quantification of the unfolded protein response with cellular resolution.Scientific reports · 2024Article
- Rescue of secretion of rare-disease-associated misfolded mutant glycoproteins in UGGT1 knock-out mammalian cells.Traffic (Copenhagen, Denmark) · 2024Article
- Rescue of secretion of a rare-disease associated mis-folded mutant glycoprotein inbioRxiv : the preprint server for biology · 2023Article
- Multiple N-glycans cooperate in balancing misfolded BRI1 secretion and ER retention.Plant molecular biology · 2020Article
- Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.Chemical reviews · 2019Article
- EFR-Mediated Innate Immune Response inGenes · 2018Article
- Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides.The Journal of biological chemistry · 2018Article
- Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors.PloS one · 2018Article
- Interdomain conformational flexibility underpins the activity of UGGT, the eukaryotic glycoprotein secretion checkpoint.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Transmembrane domain quality control systems operate at the endoplasmic reticulum and Golgi apparatus.PloS one · 2017Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Only native polypeptides are released from the endoplasmic reticulum (ER) to be transported at the site of activity. Persistently misfolded proteins are retained and eventually selected for ER-associated degradation (ERAD). The paradox of a structure-based protein quality control is that functional polypeptides may be destroyed if they are architecturally unfit. This has health-threatening implications, as shown by the numerous "loss-of-function" proteopathies, but also offers chances to intervene pharmacologically to promote bypassing of the quality control inspection and export of the mutant, yet functional protein. Here we challenged the ER of human cells with four modular glycopolypeptides designed to alert luminal and membrane protein quality checkpoints. Our analysis reveals the unexpected collaboration of the cytosolic AAA-ATPase p97 and the luminal quality control factor UDP-glucose:glycoprotein glucosyltransferase (UGGT1) in a novel, BiP- and CNX-independent checkpoint. This prevents Golgi transport of a chimera with a native ectodomain that passes the luminal quality control scrutiny but displays an intramembrane defect. Given that human proteopathies may result from impaired transport of functional polypeptides with minor structural defects, identification of quality checkpoints and treatments to bypass them as shown here upon silencing or pharmacologic inhibition of UGGT1 or p97 may have important clinical implications.
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