ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α

Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1α or ATF6α signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein α (Gadd45α) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45α abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45α expression was knocked down. In conclusion, GADD45α is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2α signaling pathway.