ER Stress-Induced Clearance of Misfolded GPI-Anchored Proteins via the Secretory Pathway

• Published in: Cell Vol. 158; no. 3; pp. 522 - 533
• Main Authors: Satpute-Krishnan, Prasanna, Ajinkya, Monica, Bhat, Savithri, Itakura, Eisuke, Hegde, Ramanujan S., Lippincott-Schwartz, Jennifer
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.07.2014; Cell Press
• Subjects: Animals; Cell Line; Endoplasmic Reticulum Stress; Humans; Lysosomes - metabolism; Mice; Prions - metabolism; Protein Folding; Rats; Secretory Pathway; Unfolded Protein Response
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.06.026

Proteins destined for the cell surface are first assessed in the endoplasmic reticulum (ER) for proper folding before release into the secretory pathway. This ensures that defective proteins are normally prevented from entering the extracellular environment, where they could be disruptive. Here, we report that, when ER folding capacity is saturated during stress, misfolded glycosylphosphatidylinositol-anchored proteins dissociate from resident ER chaperones, engage export receptors, and quantitatively leave the ER via vesicular transport to the Golgi. Clearance from the ER commences within minutes of acute ER stress, before the transcriptional component of the unfolded protein response is activated. These aberrant proteins then access the cell surface transiently before destruction in lysosomes. Inhibiting this stress-induced pathway by depleting the ER-export receptors leads to aggregation of the ER-retained misfolded protein. Thus, this rapid response alleviates the elevated burden of misfolded proteins in the ER at the onset of ER stress, promoting protein homeostasis in the ER. [Display omitted] •Stress induces rapid ER export and degradation of misfolded GPI-anchored proteins•ER export of misfolded GPI-anchored proteins relies on Tmp21•Misfolded GPI-anchored proteins transit the cell surface en route to lysosomes•ER export of misfolded GPI-anchored proteins prevents aggregation in ER during stress A previously unappreciated protective mechanism to alleviate acute ER stress has been identified. This ER stress-induced pathway triggers the export of misfolded GPI-anchored proteins, including disease-related prion mutants, for subsequent degradation in lysosomes.