The unfolded protein response (UPR) is activated as a consequence of alterations to ER homeostasis. It upregulates a group of ER chaperones and cochaperones, as well as other genes that improve protein processing within the secretory pathway. The UPR effector ATF6 alpha augments-but is not essential for-maximal induction of ER chaperones during stress, yet its role, if any, in protecting cellular function during normal development and physiology is unknown. A systematic analysis of multiple tissues from Atf6 alpha(-/-) mice revealed that all tissues examined were grossly insensitive to loss of ATF6 alpha. However, combined deletion of ATF6 alpha and the ER cochaperone p58(IPK) resulted in synthetic embryonic lethality. These findings reveal for the first time that an intact UPR can compensate for the genetic impairment of protein folding in the ER in vivo. The also expose a role for p58(IPK) normal embryonic development. (C) 2013 Elsevier Inc. All rights reserved.