Manipulating the quality of proteins
Small molecules that regulate the cell’s response to unfolded proteins have the potential to treat a variety of human diseases.
Newly made proteins must be folded into specific three-dimensional shapes before they can perform their roles in cells. Many proteins are folded in a cell compartment called the endoplasmic reticulum. The cell closely monitors the quality of the work done by this compartment. If the endoplasmic reticulum has more proteins to fold than it can handle, unfolded or misfolded proteins accumulate and trigger a stress response called the unfolded protein response. This increases the capacity of the endoplasmic reticulum to fold proteins to match the demand. However, if the stress persists, then the unfolded protein response instructs the cell to die to protect the rest of the body.
A protein called ATF6α is one of three branches of the unfolded protein response. This protein is found in the endoplasmic reticulum where it is inactive. Endoplasmic stress causes ATF6α to move from the endoplasmic reticulum to another compartment called the Golgi apparatus. There, two enzymes cut ATF6α to release a fragment of the protein that then moves to the nucleus to increase the production of the machinery needed to fold proteins in the endoplasmic reticulum.
Errors in protein folding can cause serious diseases in humans and other animals. Drugs that target ATF6α might be able to regulate part of the unfolded protein response to treat these diseases. However, no drugs that act on ATF6α had been identified. Now, two groups of researchers have identified small molecules that specifically target ATF6α.
Ciara Gallagher and colleagues screened over 100,000 compounds for their ability to reduce the activity of ATF6α-regulated genes. The experiments reveal that a class of small molecules termed Ceapins can selectively block the activity of ATF6α during endoplasmic reticulum stress, but had no effect on other proteins involved in the unfolded protein response. Furthermore, when human cells experiencing stress were treated with Ceapins, a greater number of cells died in comparison to cells that had not received Ceapins. An accompanying study by Gallagher and Peter Walter reports on the mechanism by which Ceapins act on ATF6α.
In related work, Lars Plate and colleages used a new approach to screen over 600,000 small molecules and identified a small number that could activate ATF6-regulated genes without inducing global endoplasmic reticulum stress. Further experiments tested whether any of these ATF6 drug candidates could prevent the release of incorrectly folded versions of two particular proteins from cells that are associated with types of amyloid disease in humans. One of the small molecules tested effectively reduced the release of these proteins and prevented harmful deposits of the proteins forming in the spaces surrounding cells.
Together, these findings may lead to the development of new drugs for treating diseases associated with incorrect protein folding in the endoplasmic reticulum.
To find out more
Read the eLife research papers on which this eLife digest is based: “Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch”, “Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress” and “Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation” (July 20, 2016).
Read a commentary on these research papers: “Unfolded protein response: Modulating protein quality control”.