Protein folding and quality control in the ER

The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding andmodification of secretoryandmem-brane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease. The endoplasmic reticulum (ER) serves as aprotein-folding factory where elaborate quality and quantity control systems monitor an efficient and accurate production of secretory and membrane proteins, and constantly main-tain proper physiological homeostasis in the ER including redox state and calcium balance. In this article, we present an overview the recent progress on the ER quality control system, mainly focusing on the mammalian system. TRANSLATION OF ER-TARGETED PROTEINS Most mammalian secretory and membrane proteins are cotranslationally imported into the ER (Fig. 1A). Signal sequence on the newly synthesized polypeptides are caught by the signal-recognition particle (SRP), whose bind-ing slows protein synthesis in a process known as elongation arrest, and directs polypeptides to the translocon, composed of the Sec61abg complex in the ER membrane (Johnson and Van Waes 1999; Saraogi and Shan 2011). After arriving at the translocon, translation resumes in a process called cotranslational translocation (Hegde and Kang 2008; Zimmermann et al. 2010). Numerous ER-resident chaperones and enzymes aid in structural and conformational maturation necessary for proper protein fold-ing, including signal-peptide cleavage, N-linked glycosylation, disulfide bond formation, and glycophosphatidylinositol (GPI)-anchor addi-tion (Ellgaard and Helenius 2003). Recently, the synthesis of posttranslationally inserted proteins, known as tail-anchored (TA) proteins, was elucidated (Fig. 1B) (Rabu et al