Many of the proteins that are inserted into the ER lumen or into the ER membrane are not residents of this organelle and so must be transported to other intracellular sites, or be secreted. About 20 years ago, it became apparent that proteins entering the ER are subjected to a quality-control mechanism that allows only correctly folded and (when applicable) assembled polypeptides to be transported to their final destination (reviewed in Ellgaard and Helenius 2003). It was later realized that rather than being degraded within the lumen of the ER, soluble and membrane bound secretory proteins that fail to fold are destroyed after being dislocated to the cytosol, where they become substrates of proteasomes. Thus, although the vacuole can also contribute to the disposal of ER and secretory proteins (Hong et al. 1996; Tamura et al. 2004), retention and proteasomal degradation appears to be a common mechanism that cells use to avoid the potentially dangerous expression of aberrant polypeptides. This disposal pathway is often referred to as ER-associated protein degradation (ERAD) and considerable progress has been made during the last decade towards understanding its individual steps at the molecular level.
Different mechanisms can contribute to the retention of misfolded proteins in the ER. One of them could be the absence of an exposed export signal. According to current models, export of proteins from the ER can occur by bulk-flow or can be mediated by receptors that recognize specific signals on the exported proteins (see chapt. by Aniento et al., this volume). If these signals are not exposed on the surface of the molecule because of misfolding, the protein will be retained in the folding compartment. The retention ofunfolded proteins in the ER can also be due to their association with molecular chaper-ones, which in turn are maintained in the ER at steady state because they bear signals for retrieval from downstream compartments or because they form an insoluble matrix and are therefore excluded from budding vesicles.
A role for protein trafficking in the ERAD pathway is suggested by the finding that a generalized block in the transport of proteins to the Golgi complex can inhibit the degradation of certain substrates (reviewed in Ahner and Brodsky 2004). In addition, it has been shown that certain misfolded proteins can leave the ER in transport vesicles only to be returned prior to degradation (Vashist et al. 2001; Yamamoto et al. 2001; Sato et al. 2004). However, since a block in protein transport can also have a direct impact on ER structure and homeostasis, it remains to be established whether certain proteins must recycle from the Golgi to be degraded, or whether the observed effects are due to a general perturbation of ER functions.
In certain cases, aggregation can contribute to the retention of unfolded protein in the ER. Misfolded proteins are often aggregation prone, and their inclusion in large complexes is likely to limit their diffusion through the ER and their insertion into transport vesicles. While in some cases aggre gate formation does not hamper the subsequent degradation of the misfolded polypeptide (Molinari et al. 2002), in other cases the ER seems to be unable to efficiently disrupt such complexes, leading to the prolonged accumulation of the misfolded proteins (Sparvoli et al. 2001).
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