Fig. 4

STC2 modulates the severity of ER stress response, promotes cell survival and prevents apoptosis. Hypoxia, nutrient depletion associated ATP depletion, and oxidative stress trigger ER stress. Similarly, therapeutic treatment and some compounds disrupting ER functions also trigger ER stress. Under such conditions, BiP, the negative regulator of ATF6, PERK and IRE1, is sequestrated by misfolded proteins accumulated in the ER lumen. The activation of ATF6 (tATF6, truncated and activated form), ATF4 and XBP1 leads to transcriptional upregulation of genes involved in ER homeostasis, ER biogenesis, inflammatory response, protein folding and degradation. Severe and prolonged ER stress leads to the activation of JNK/NF-κB and CHOP pathways which promote apoptosis. Under moderate stress conditions, the p-eIF2α-ATF4 axis serves as a modulator of the severity of ER stress response by activating three down stress genes: 1) as the negative regulator of ER stress, BiP upregulation facilitates restoring ER homeostasis; 2) GADD34, a phosphoprotein phosphatase, directly dephosphorylates eIF2α to attenuate ATF4-mediated stress response; and 3) importantly, STC2 performs its function through affecting ATF4 or calcineurin, a calcium and calmodulin dependent serine/threonine protein phosphatase that is evidenced by the report showing aluminium toxicity causes ER stress, which activates IRE1β, but not ATF4, finally leading to apoptosis