Journal
IEE PROCEEDINGS SYSTEMS BIOLOGY
Volume 152, Issue 4, Pages 285-289Publisher
INST ENGINEERING TECHNOLOGY-IET
DOI: 10.1049/ip-syb:20050048
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Funding
- NIGMS NIH HHS [R01GM065507, R01 GM065507-03, R01 GM065507] Funding Source: Medline
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The overexpression of secreted proteins is of critical importance to the biotechnology and biomedical fields. A common roadblock to high yields of proteins is in the endoplasmic reticulum (ER) where proofreading for properly folded proteins is often rate limiting. Heterologous expression of secreted proteins call saturate the cell's capacity to properly fold protein, initiating the unfolded protein response (UPR), and resulting in a loss of protein expression. An obvious method for overcoming this block would be to increase the capacity of the folding process (overexpressing chaperones) or decreasing the proofreading process (blocking the down-regulation by the UPR). Unfortunately, these processes are tightly interlinked, whereby modification of one mechanism has unknown effects on the other. Although some success has been achieved in improving expression via co-overexpressing ER chaperones, the results have not lead to a global method for increasing all heterologously overexpressed proteins. Further, many diseases have been linked to extended periods of stress and are not treatable by these approaches. This work utilises both experimental analysis of the interactions within the ER and modelling in order to understand how these interactions affect early secretory pathway dynamics. This study shows that overexpression of the ER chaperone binding protein does not regulate Ire1p and the UPR as predicted by a model based on the published understanding of the molecular mechanism. A flew model is proposed for Ire1p regulation and the UPR that better fits the experimental data and recent studies on Ire1p.
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