Vacuole

Enzyme

Autophagy

Proteasome

Biology

Gene

Biogenesis

Golgi apparatus

Secretory protein

Endoplasmic reticulum

Endoplasmic-reticulum-associated protein degradation

Unfolded protein response

Cytoplasm

Apoptosis

Protein folding

Aggresome

Protein quality

Lysosome

Protein degradation

Cell biology

Secretion

Biochemistry

Secretory pathway

The Journal of Cell Biology

Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.

Protein quality control in the secretory pathway