Unfolded protein response

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... 

Unfolded protein response, when mis-folded proteins accumulate in the ER, signal transduction pathways are activated that increase the biosynthetic capacity and decrease the biosynthetic burden of the ER. 

Sims, A.H., Gent, M.E., Lanthaler, K. et al. (2005) Transcriptome analysis of recombinant protein secretion by Aspergillus nidulans and the unfolded-protein response in vivo. Applied and Environmental Microbiology, 71 (5), 2737-2747. 

Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., and Ron, D. (2000). Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897-904. 

Scheuner, D., Song, B., McEwen, E., Liu, C., Laybutt, R., Gillespie, P., Saunders, T., Bonner-Weir, S., and Kaufman, R. J. (2001). Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165—1176. 

PMP-22 gene (Ch. 38). Because the function of PMP-22 is uncertain, the mechanisms by which the point mutations in this protein cause the trembler phenotype are unclear. However, as with the PLP mutations, the pathology may result from an unfolded protein response to abnormal protein that is retained in the endoplasmic reticulum. 

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. 

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. 

ER function, as can external agents such as calcium ionophores and chemical toxicants (Rao, et al., 2001) which can cause ER stress. ER responds to stress by triggering a specific signalling pathway termed the unfolded protein response (UPR). The UPR serves to protect the cell from normal variations that occur in the cellular environment (Ma, et al., 2004, Rao, et al., 2001). Recent evidence suggests that the UPR can also be activated in tumours (Ma, et al., 2004). 

Patil C., and Walter P. 2001 Intracellular signaling from the endoplasmic reticulum to the nucleus the unfolded protein response in yeast and mammals. Curr Opin Cell Biol 13, 349—355. 

UPR VA VDAC VNA WD-40 repeats unfolded protein response viable apoptotic cell voltage-dependent anion channel viable nonapoptotic cell repeated sequence of approximately 40 amino acids, usually tryptophan (W) and aspartate (D) residues... 

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]...

It has been shown in cell culture models of cXj-antitrypsin that Z-oq-antitrypsin in the ER causes expression of a novel set of stress genes with products that have the role of restoring ER function to normal. Z-a,-Antitrypsin induces two signal transduction pathways the ER overload response and unfolded protein response pathways. Via these transduction pathways, the presence of Z-oq-antitrypsin, as opposed to M-(Xj-antitrypsin, induces an hepatic inflammatory response. It is thought that this ER-specific stress response results in hepatic injury. 

Carman, G.M., and Henry, S.A., 1999, Phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and interrelationship with other metabolic processes. Prog. Lipid Res. 38 361-399. Chang, H.J., 2001, Role of the unfolded protein response pathway in phospholipid biosynthesis and membrane trafficking in Saccharomyces cerevisiae. Department of Biological Sciences, Carnegie Mellon University. 

Cox, J.S., Chapman, R.E., and Walter, P., 1997, The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane. Mol. Biol. CellS 1805-1814. 

Cox, J.S., and Walter, R, 1996, A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87 391 —404. 

Jesch, S.A., Zhao, X., Wells, M.T., and Henry, S.A., 2005, Genome-wide analysis reveals inositol, not choline, as the major effector of Ino2p-Ino4p and unfolded protein response target gene expression in yeast. J. Biol. Chem. 280 9106-9118. 

Kawahara, T., Yanagi, H., Yura, T., and Mori, K., 1997, Endoplasmic reticulum stress-induced mRNA splicing permits synthesis of transcription factor Haclp/Ern4p that activates the unfolded protein response. Mol. Biol. Cell 8 1845-1862. 

In some mutants and transgenic mice overexpressing PLPl, there is an accumulation of PLP in the endoplasmic reticulum of the oligodendrocyte, which may eventually trigger apoptosis. The latter is related to an unfolded protein response, UPR (Gow and Sharma, 2003). In these forms, increasing the level of PLP may exacerbate pathology (Gow et al., 1998). 

Goldberg JL, Barres BA (2000) Nogo in nerve regeneration. Nature 403 369-370 Gow A, Sharma R (2003) The unfolded protein response in protein aggregating diseases. Neuromolecular Med 4 73-94... 

---