ER-associated protein degradation

Friediander, R., Jarosch, E., Urban, J., VoLKWEiN, C., and Sommer, T. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nature Cell Biol. 2000, 2, 379-84. 

Mayer TU, Braun T, Jentsch, S (1998) Role of the proteasome in membrane extraction of a short-lived ER-transmembrane protein. EMBO ] 17 3251-3257 McCracken AA, Brodsky JL (1996) Assembly of ER-associated protein degradation in vitro dependence on cytosol, calnexin, and ATP. J Cell Biol 132 291-298 McDonald HB, Byers B (1997) A proteasome cap subunit required for spindle pole body duplication in yeast. J Cell Biol 137 539-553 McGee TP, Cheng HH, Kumagai H, Omura S, Simoni RD (1996) Degradation of 3-hydroxy-3-methylg utaryl-CoA reductase in endoplasmic reticulum membranes is accelerated as a result of increased susceptibility to proteolysis. J Biol Chem 271 25630-25638... 

After activation of the ER stress sensors, IREl, PERK and ATF6, distinct signaling pathways are induced to regulate ER chaperones expression, degradation of protein through the ER associated protein degradation (ERAD) and expansion of the ER. If these events fail to restore ER homeostasis, Ca2-l- is released to activate apoptotic signaling pathways. 

McCracken, A.A., Brodsky, J.L. Assembly of ER-Associated Protein Degradation In Vitro Dependence on Cytosol, Calnexin, and ATP J. Cell Biol. 19% 132, 291-298. 

Chaperones. Figure 2 The multiple roles of BiP in the biogenesis of the secretory proteins. BiP, immunoglobulin heavy chain binding protein ER, endoplasmic reticulum ERAD, ER-associated degradation ERj, resident ER protein with J-domain Sec61, core subunit of the protein translocase UPR, unfolded protein response that involves several signal transduction pathways that are activated in order to increase the biosynthetic capacity and decrease the biosynthetic burden of the ER... 

ER-Associated Degradation, when proteins mis-fold in the ER due to mutation or environmental conditions, they are selectively exported to the cytosol for degradation by the proteasome. 

Travers, K. J., Path, C. K., Wodicka, L, Lockhart, D. J., Weissman, J. S., and Walter, P. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 2000, 101, 249-58. 

Hampton, R. Y. ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol 2002, 34, 476-82. 

Although ER protein degradation seems not be essential for yeast cells, the breakdown of mutated and thus malfolded ER proteins is often associated with severe diseases in human (Ciechanover, 1998 Plemper and Wolf, 1999). The importance of this process in the understanding of genetic disorders like cystic fibrosis and a 1-antitrypsin deficiency has been outlined above. In the following we will give further examples on how viruses or toxins may misuse the machinery for the ER protein degradation to interfere with cellular processes. 

Fig. 12.3 The unfolded proteins in the endoplasmic reticulum turn on the unfolded protein response (UPR) and ER-associated degradation (ERAD). The presented model was adapted from McCracken and Brodsky [59]...

Oda, Y, Okada, T, Yoshida, H., Kaufman, R.J., Nagata, K. and Mori, K. (2006) Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J. Cell Biol. 172, 383-393. 

Nakatsukasa, K., Huyer, G., Michaelis, S., and Brodsky, J.L. (2008) Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell, 132, 101-112. 

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