Nascent polypeptide chains, synthesized by cytoplasmic ribosomes, enter the ER lumen at specialized sites in the ER membrane called translocons, which are complexes of several ER membrane proteins

In eukaryotic cells, most proteins destined for membrane insertion or secretion are first processed in the endoplasmic reticulum (ER). Nascent polypeptide chains, synthesized by cytoplasmic ribosomes, enter the ER lumen at specialized sites in the ER membrane called translocons, which are complexes of several ER membrane proteins that associate to form a pore (Schnell and Herbert, 2003). Sec61, Sec61 and Sec61 form the pore, and this trimeric complex is associated with other proteins including ERj1, Sec62 and Sec63 in mammals (Meyer et al., 2000; Zimmermann et al., 2006). Mutations in SEC63 cause polycystic liver disease (PCLD) in humans, a progressive disorder characterized by the presence of many (>20) cysts throughout the liver (Davila et al., 2004; Everson et al., 2004). PCLD often co-occurs in patients with autosomal dominant polycystic kidney disease (PCKD), but can also exist as a separate disease without kidney cysts (Torres et al., 2007). Polycystic livers can grow up to ten times their normal size, resulting in significant patient morbidity. Although a few therapeutic interventions are available to slow cyst growth, only liver transplantation can change the course of the disease (Drenth et al., 2010). It remains unclear how mutations in SEC63 cause liver cysts, but possibilities include disrupted trafficking of vital proteins such as polycystin-1, an integral cilia membrane protein mutated in PCKD (Fedeles et al., 2011) and disrupted tethering of proteins to the cytosolic face of the ER (Müller et al., 2010). Another possibility is that disruption of SEC63 triggers ER stress that contributes to the pathophysiology of PCLD. Nascent polypeptides are transported across the ER translocon for processing, folding and maturation (Rapoport, 2007). An imbalance between the load of unfolded preproteins that enter the ER and the capacity of this organelle to properly process the load results in ER ‘stress’: in this case an accumulation of misfolded proteins in the ER lumen (Ron and Walter, 2007). This activates the unfolded protein response (UPR), a conserved cellular homeostatic mechanism, in an attempt to reconcile the imbalance. If the imbalance persists, the UPR can ultimately lead to cell death (Ron and Walter, 2007). Not surprisingly, elevation of ER stress and activation of the UPR are implicated in the pathology of many diseases, including myelin disorders such as multiple sclerosis and Charcot-Marie-Tooth disease (D’Antonio et al., 2009; Lin and Popko, 2009). Myelin is a multilayered membrane formed by the wrapping of glial cells around axons that allows for efficient conduction of action potentials in the vertebrate nervous system (Nave and Trapp, 2008). Specialized glial cells generate the myelin sheath: oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). Myelin is formed as an elaboration of the plasma membrane of the glial cells, which must generate tremendous amounts of membrane proteins and lipids (Anitei and Pfeiffer, 2006). Segments of myelin are separated by