Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of GADD34.

Disruption in endoplasmic reticulum (ER) function, termed ER stress, occurs in many diseases, including neurodegenerative disorders, diabetes, and cancer. Cells respond to ER stress with the unfolded protein response (UPR), which triggers a broad transcriptional program to restore and enhance ER function. Here, we found that ER stress up-regulates the mRNA encoding the developmentally regulated transcriptional repressor hairy and enhancer of split 1 (HES1), in a variety cell types. Depletion of HES1 increased cell death in response to ER stress in mouse and human cells, in a manner that depended on the pro-apoptotic gene growth arrest and DNA damage-inducible protein GADD34 (also known as Protein phosphatase 1 regulatory subunit 15A, or MyD116). Furthermore, HES1 bound to the GADD34 promoter, and its depletion led to an up-regulation of GADD34 expression during ER stress. Our results identify HES1 as a repressor of GADD34 expression, and reveal that HES1 contributes to cell fate determination in response to ER stress.