Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

摘要

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 compartment called the endoplasmic reticulum before being transported to their final location. However, if a cell suddenly needs to make a large number of new proteins, it can overwhelm the endoplasmic reticulum and unfolded proteins may accumulate. The cell responds to this stress by activating the unfolded protein response, which increases the folding capacity of the endoplasmic reticulum 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 ATF6 is involved in one branch of the unfolded protein response. Endoplasmic reticulum stress causes ATF6 to move from the endoplasmic reticulum to another cell compartment where certain enzymes are able to cut the protein. A fragment of ATF6 then moves to the nucleus of the cell to activate genes needed to increase the cell’s capacity to fold proteins. Errors in protein folding can cause serious diseases in humans and other animals. Drugs that target ATF6 might be able to regulate part of the unfolded protein response to treat these diseases. However, no drugs that act on ATF6 had been identified. Now, two groups of researchers have independently identified small molecules that specifically target ATF6. Plate et al. 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. In an independent study, Gallagher et al. identified a type of small molecule that can inhibit the activity of ATF6. Together, these findings may lead to further development of new drugs for treating diseases associated with incorrect protein folding in the endoplasmic reticulum.