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unfolded protein response

Saturday 14 January 2006

The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, cumulatively called the unfolded protein response (UPR).

Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids.

The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.

- Folding in the endoplasmic reticulum (ER) must couple protein-synthesis pathways operating outside of the compartment with ER-assisted folding (ERAF) pathways in the lumen.

- Chaperone-mediated folding imbalances that are associated with numerous misfolding diseases, including diabetes, trigger the unfolded-protein response (UPR), using both transcriptional and translational pathways to correct the problem.

- Small-molecule inhibitors could be useful to help rebalance protein synthesis with ERAF pathways through the ribosomal initiating factor eIF2alpha. Reprogramming stress pathways with drugs provides a potential new approach for balancing ER-protein load with cellular-folding capacity, thus correcting disease.

See also

- unfolded protein

References

- Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29. PMID: #17565364#

- Wiseman RL, Balch WE. A new pharmacology—drugging stressed folding pathways. Trends Mol Med. 2005 Aug;11(8):347-50. PMID: #16005683#

- Kaufman RJ: Orchestrating the unfolded protein response in health and disease. J Clin Invest 110:1389, 2002.

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

- Ma Y, Hendershot LM: The unfolding tale of the unfolded protein response. Cell 107:827, 2001.