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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.

A novel UGGT1 and p97-dependent checkpoint for native ectodomains with ionizable intramembrane residue