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 unfolded proteins as part of the activation process. However, evidence for an unfolded protein-independent mechanism has recently emerged, suggesting that UPR can be activated by multiple modes. Importantly, dysregulation of the UPR has been linked to human diseases including Type II diabetes, heart disease, and cancer. The existence of alternative regulatory pathways for UPR sensors raises the exciting possibility for the development of new classes of therapeutics for these medically important proteins.
Highlights
Nascent secretory proteins enter the endoplasmic reticulum (ER) lumen and immediately encounter a myriad of quality control (QC) effectors that enhance correct protein folding and prevent and resolveCells 2012, 1 accumulation of misfolded secretory proteins in the ER [1,2]
The spliced HAC1 output can be measured by multiple assays including Northern blot of spliced mRNA, RT PCR of spliced and unspliced mRNA, fluorescent signal from the product of an out of translational reading frame fluorescent protein mRNA that Ire1p splices into frame, changes in transcript levels of a Hac1p transcription factor targeted gene (i.e., INO1 or KAR2), measurement of fluorescence or E-galactosidase activity produced by a transcriptional reporter containing a Unfolded Protein Response (UPR)
The emerging picture of Ire1p regulation is that peptide binding to the major histocompatibility complex 1 (MHC1)-like groove can enhance the rate of Ire1p activation and its splicing activity in yeast
Summary
Nascent secretory proteins enter the endoplasmic reticulum (ER) lumen and immediately encounter a myriad of quality control (QC) effectors that enhance correct protein folding and prevent and resolve. S. cerevisiae [5]) and IRE1D (highly homologous to the yeast Ire1p), PERK, and ATF6) [6±9] in metazoans. Each UPR stress sensor has a discrete set of downstream targets that help a cell resolve an unfolded protein burden [3,4,10,11]. XBP1 (Ire1p cleaves HAC1) mRNA and a tRNA ligase splices the transcription factor in frame, enabling the correctly spliced form to upregulate chaperones and ERAD components [6,15]. If the metazoan UPR fails to resolve the stress, caspases can be activated leading to cell death [18]. For this reason, UPR resolution is considered critical for a cell survival. Increased levels of Hac1p upregulate UPR effectors leading to resolution of stress
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