1. Cell Biology
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Unfolded Protein Response: Modulating protein quality control

  1. Lars Plate
  2. Ryan J Paxman
  3. R Luke Wiseman  Is a corresponding author
  4. Jeffery W Kelly  Is a corresponding author
  1. The Scripps Research Institute, United States
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Cite this article as: eLife 2016;5:e18431 doi: 10.7554/eLife.18431
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Small molecules modulate protein folding in the endoplasmic reticulum and influence disease.

Many proteins are folded inside a compartment called the endoplasmic reticulum (ER) before being secreted from the cell. Misfolded proteins in the endoplasmic reticulum activate the stress-sensor protein ATF6, which upregulates genes that increase the capacity of the endoplasmic reticulum to fold proteins. ATF6 signaling is often active for extended periods of time in cancer cells and virus-infected cells, which enables these cells to fold large numbers of proteins needed for the cancer or virus to spread. The Ceapin molecules reported by Gallagher et al. can inhibit this chronic ATF6 signaling, and make these cells more sensitive to endoplasmic reticulum stress. In our study, we identified a set of small molecules that activate ATF6 signaling and increase the capacity of the endoplasmic reticulum to fold proteins in the absence of stress. These molecules can reduce the secretion of misfolded proteins that are associated with amyloid diseases, and possibly prevent other protein folding diseases.

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