ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress

In vertebrates, three proteins--PERK, IRE1alpha, and ATF6alpha--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 Atf6alpha in the mouse. ATF6alpha is neither essential for basal expression of ER protein chaperones nor for embryonic or postnatal development. However, ATF6alpha 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 Atf6alpha null animals in vivo compromises organ function and survival despite functional overlap between UPR sensors. These results suggest that the vertebrate ATF6alpha 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.     

Unfolding protein response signaling is involved in development,maintenance, and regression of the corpus luteum during the bovine estrous cycle

The corpus luteum (CL) is a transient endocrine organ. Development, maintenance, and regression of CL are effectively controlled by dynamic changes in gene expression. However, it is unknown what types of gene are affected during the CL life span of the estrous cycle in bovine. Here, we determined whether unfolded protein response (UPR) signaling via eIF2α/ATF4/GADD34, p90ATF6/p50ATF6, and IRE1/XBP1, which is a cellular stress response associated with the endoplasmic reticulum (ER), is involved in the bovine CL life span. Our results indicated that expression of Grp78/Bip, the master UPR regulator, was increased during the maintenance stage and rapidly decreased at the regression stage. Additionally, UPR signaling pathways genes were found to be involved in luteal phase progression during the estrous cycle. Our findings suggested that Grp78/Bip, ATF6, and XBP1 act as ER chaperones for initiating CL development and maintaining the CL. In addition, we investigated whether ER stress-mediated apoptosis is occurred through three UPR signaling pathways in CL regression stage. Interestingly, pIRE1 and CHOP were found to be involved in both the adaptive response and ER stress-mediated apoptosis. During the CL regression stage, increased expression of pJNK and CHOP, two components of ER stress-mediated apoptotic cascades, occurred before increased level of cleaved caspase 3 were observed. The present investigation was performed to identify a functional link between UPR signaling and CL life span during the bovine estrous cycle. Taken together, results from this study demonstrated that UPR protein/gene expression levels were different at various stages of the bovine CL life span. Variations in the expression of these protein/genes may play important roles in luteal stage progression during the estrous cycle.