Circadian control of stress granules by oscillating EIF2α

Stress granule formation is important for stress response in normal cells and could lead to chemotherapy resistance in cancer cells. Aberrant stress granule dynamics are also known to disrupt proteostasis, affect RNA metabolism, and contribute to neuronal cell death. Meanwhile, circadian abnormality is an aging-related risk factor for cancer and neurodegeneration. Whether stress granule dynamics are circadian regulated is entirely unknown. Here we show that the formation of stress granules varied by zeitgeber time in mouse liver. Moreover, altering circadian regulation by silencing the core circadian gene Bmal1 in a cell line expressing an endogenous GFP-tagged G3BP1 significantly increased stress granule dynamics, while the overexpression of Bmal1 decreased them. Surprisingly, increased stress granule dynamics and formation by transient decrease of BMAL1 coincided with increased resistance to stress-induced cell death. The circadian regulation of stress granules was mediated by oscillating eIF2 alpha expression. At zeitgeber time when BMAL1 and eIF2 alpha were at nadir, reduction of unphosphorylated eIF2 alpha could significantly alter the ratio of phosphorylated/ total eIF2 alpha and quickly lead to increased formation of stress granules. Therefore, diurnal oscillating eIF2 alpha connects the circadian cue to a cellular stress response mechanism that is vital for both neurodegeneration and cancer.