Degradation of endoplasmic reticulum (ER) quality control substrates requires transport between the ER and Golgi. This paper and reference 17 show that soluble, misfolded ER proteins must first be transported from the ER to the Golgi before they can be degraded.Ĭaldwell, S. Distinct retrieval and retention mechanisms are required for the quality control of endoplasmic reticulum protein folding. Role of ATP and disulphide bonds during protein folding in the endoplasmic reticulum.
Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum. Symptoms of cellular indigestion? EMBO Rep. An address on a characteristic organism of cancer. The table indicates that different degradation pathways exist. Components that are required and not required for their degradation are listed. This review gives a list of ER-associated degradation substrates in yeast. ER protein quality control and proteasome-mediated protein degradation. Reference 10 first showed a cytosolic requirement for the degradation of a soluble ER protein.īrodsky, J. This report and reference 74 describe in vitro systems for the degradation of ER-associated proteins. Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. ER quality control: the cytoplasmic connection. Protein degradation in the endoplasmic reticulum. Targeting of the yeast plasma membrane ATPase: a novel gene AST1 prevents mislocalization of mutant ATPase to the vacuole. A pathway for targeting soluble misfolded proteins to the yeast vacuole. A regulatory link between ER-associated protein degradation and the unfolded-protein response. cerevisiae requires an intact unfolded protein response pathway. Degradation of proteins from the ER of S. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Tripartite management of unfolded proteins in the endoplasmic reticulum. These ATPases might 'pull' polypeptides out of the membrane in a similar manner to AAA proteases, which remove misfolded membrane proteins in bacteria and mitochondria.
Recent experiments indicate a role for a member of the AAA family of ATPases - Cdc48 in yeast and p97 in mammals - in extracting polypeptides from the ER membrane. However, polyubiquitylation alone is insufficient to release a substrate into the cytosol. The ubiquitylation machinery comprises both specific conjugation and ligase enzymes. Polypeptide substrates that emerge from the translocation channel are polyubiquitylated at the membrane. Given the size limitation of the Sec61 channel, it is likely that substrates need to be at least partially unfolded before they can pass through the channel.
On the basis of biochemical and genetic data, transport of the polypeptide seems to occur through the protein-conducting channel that is formed by the Sec61 complex. The next step in retro-translocation is the transport of the polypeptide chain across the ER membrane. BiP and other chaperones have also been implicated in targeting misfolded substrates for retro-translocation. An important player seems to be protein disulphide isomerase and its relatives. Exposure of hydrophobic polypeptide patches might represent the general recognition signal and ER chaperones might be the signal receptors. The first step in retro-translocation is the recognition of a misfolded substrate. It is also used by some plant and bacterial toxins to enter the cytosol of cells. The retro-translocation pathway is co-opted by certain viruses to degrade proteins that are involved in the immunoprotection of the host. Recent evidence indicates that misfolded proteins are retro-translocated from the ER lumen to the cytosol and are then degraded by the ubiquitin–proteasome system. Misfolded proteins that cannot be brought back to their native state are degraded. An elaborate system of chaperones helps proteins to fold and prevents misfolded polypeptides from reaching their final destination. When newly synthesized proteins translocate into the endoplasmic reticulum (ER) lumen, they undergo 'quality control'.
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