Louise Wasley

Protein Retention in the Endoplasmic Reticulum Mediated by GRP78

Proteins destined for secretion in mammalian cells transit the secretory pathway consisting of two major compartments: the endoplasmic reticulum (ER) and Golgi complex (GC) (Fig. 8.1). Proteins are first cotranslationally translocated into the lumen of the ER. The ER is the site of initial processing events that are crucial for proper folding of the nascent polypeptide. These processing events include signal peptide cleavage (1), addition of core N-linked oligosaccharides at consensus recognition sites (2), and disulfide bond formation mediated by protein disulfide isomerase (3). Attaining an appropriate conformation is essential for a protein to be efficiently transported from the ER to the GC (4). For most proteins, transport from the ER to the GC is the rate-limiting step for secretion (5, 6). This transport step requires ATP (7). Retention in the ER, and eventual degradation, is the fate of many secretion-incompetent proteins (8).