unfolded protein responses with or without unfolded proteins展开的蛋白质反应有或没有展开的蛋白质.pdf

Cells 2012, 1, 926-950; doi:10.3390/cells1040926 OPEN ACCESS cells ISSN 2073-4409 /journal/cells Review Unfolded Protein Responses With or Without Unfolded Proteins? Erik L. Snapp Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; E-Mail: erik-lee.snapp@; Tel.: +718-430-2967; Fax: +718-430-8996 Received: 17 September 2012; in revised form: 15 October 2012 / Accepted: 22 October 2012 / Published: 1 November 2012 Abstract: The endoplasmic reticulum (ER) is the site of secretory protein biogenesis. The ER quality control (QC) machinery, including chaperones, ensures the correct folding of secretory proteins. Mutant proteins and environmental stresses can overwhelm the available QC machinery. To prevent and resolve accumulation of misfolded secretory proteins in the ER, cells have evolved integral membrane sensors that orchestrate the Unfolded Protein Response (UPR). The sensors, Ire1p in yeast and IRE1, ATF6, and PERK in metazoans, bind the luminal ER chaperone BiP during homeostasis. As unfolded secretory proteins accumulate in the ER lumen, BiP releases, and the sensors activate. The mechanisms of activation and attenuation of the UPR sensors have exhibited unexpected complexity. A growing body of data supports a model in which Ire1p, and potentially IRE1, directly bind unf