ATF6α optimizes long-term endoplasmic reticulum function to protect cells from chronic stress

In vertebrates, three proteins-PERK, IRE1 alpha, and ATF6 alpha - sense protein-misfolding stress in the ER and initiate ER-to-nucleus signaling cascades to improve cellular function. The mechanism by which this unfolded protein response (UPR) protects ER function during stress is not clear. To address this issue, we have deleted Atf6 alpha in the mouse. ATF6 alpha is neither essential for basal expression of ER protein chaperones nor for embryonic or postnatal development. However, ATF6 alpha is required in both cells and tissues to optimize protein folding, secretion, and degradation during ER stress and thus to facilitate recovery from acute stress and tolerance to chronic stress. Challenge of Atf6 alpha null animals in vivo compromises organ function and survival despite functional overlap between UPR sensors. These results suggest that the vertebrate ATF6 alpha pathway evolved to maintain ER function when cells are challenged with chronic stress and provide a rationale for the overlap among the three UPR pathways.