Figure 4.

Cellular impact of downstream effects of ATF6 activation. Upon ER stress, ATF6α and related ATF6β are released from tethering in the ER membrane by ER luminal GRP78 and thus allowed to proceed to the Golgi, where they undergo regulated intramembrane proteolysis by S1P and S2P, releasing the respective cytoplasmic domains, nATF6α and nATF6β. The nATF6α transcription factor is more transcriptionally potent but also has a short half-life due to rapid degradation. nATF6α and nATF6β have overlapping transcriptional signatures; both contribute to cell survival signaling as well as chaperone, redox, and ERAD support. Atf6α promotes β-cell proliferation: overexpression increases and inhibition or knockdown decreases β-cell cycling in islet cell cultures. ATF6β induces WFS1, which has prosurvival activity. ATF6α also transcriptionally induces Chop and, as such, may contribute to cell death in some contexts. Green arrows indicate transcriptional regulation. ATF6, activating transcription factor 6; nATF6, nuclear ATF6; CHOP, C/EBP homologous protein; GRP78, glucose regulated protein 78; JNK, c-Jun N-terminal kinase; circled P indicates phosphorylation; S1P, site 1 protease; S2P, site 2 protease; WFS1, Wolfram syndrome 1.