Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress

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 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. In a related study, Gallagher et al. identified a group of small molecules called Ceapins, which inhibit ATF6α activity. Here, Gallagher and Walter investigate how Ceapins act on ATF6α. The experiments show that Ceapin causes ATF6α molecules to form clusters that prevent the protein from moving to the Golgi apparatus by keeping it away from the machinery that moves proteins between these compartments. When the enzymes that cut ATF6α are sent to the endoplasmic reticulum, Ceapin treatment no longer prevents ATF6α activation, which shows that these small molecules specifically inhibit the stress-induced movement of ATF6α. When Ceapins are washed out of cells, the ATF6α clusters fall apart and ATF6α can now move to the Golgi. These experiments show that ATF6α is actively held in the endoplasmic reticulum by a mechanism that is stabilized by Ceapins. Gallagher and Walter propose that the small clusters of ATF6α in unstressed cells act to keep this protein in the endoplasmic reticulum. However, when cells experience stress, the ATF6α clusters fall apart to allow the protein to move to the Golgi. The next steps following on from this work are to find out what these clusters are, how they are influenced by endoplasmic reticulum stress and exactly how the Ceapins stabilize these clusters.