As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a
vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain
its homeostasis, the ER is equipped with an elaborate network of protein folding chaperones and
multiple quality control pathways whose cooperative actions safeguard the fidelity of protein biogenesis. However, due to genetic abnormalities, the error-prone nature of protein folding and assembly,
and/or defects or limited capacities of the protein quality control systems, nascent proteins may
become misfolded and fail to exit the ER. If not cleared efficiently, the progressive accumulation of
misfolded proteins within the ER may result in the formation of toxic protein aggregates, leading to
the so-called “ER storage diseases”. In this review, we first summarize our current understanding of
the protein folding and quality control networks in the ER, including chaperones, unfolded protein
response (UPR), ER-associated protein degradation (ERAD), and ER-selective autophagy (ER-phagy).
We then survey recent research progress on a few ER storage diseases, with a focus on the role of
ER quality control in the disease etiology, followed by a discussion on outstanding questions and
emerging concepts in the field. CLICK TO REVIEW
Keywords: ER; unfolded protein response; ER-associated protein degradation; ER-phagy; chaperone;
protein aggregate; ER storage disease