Abstract
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 eIF2α expression. At zeitgeber time when BMAL1 and eIF2α were at nadir, reduction of unphosphorylated eIF2α could significantly alter the ratio of phosphorylated/total eIF2α and quickly lead to increased formation of stress granules. Therefore, diurnal oscillating eIF2α connects the circadian cue to a cellular stress response mechanism that is vital for both neurodegeneration and cancer.
Highlights
The ability of cells to cope with environmental and cellular stress is vital for their flourishment and survival
To examine whether stress granule formation could be affected by the different time of the day in vivo, we intraperitoneally injected the mice with saline or oxidative stressor sodium arsenite and harvested the liver tissues from circadian entrained mice at zeitgeber time 5 and 13 (ZT 5 and ZT 13)
In this study, we have provided evidence to show that stress granule formation and dynamics are affected by circadian cues, and this regulation is caused by oscillating eIF2α expression
Summary
The ability of cells to cope with environmental and cellular stress is vital for their flourishment and survival. By developing various stress response and anti-apoptotic mechanisms, cancer cells can proliferate in hostile microenvironment, such as hypoxia, or even chemotherapy drugs[3]. One of the cellular stress responses that have been intimately linked to stress resistance in cancer cells and the development of some neurodegenerative diseases is the formation of stress granules[3,7,8,9]. Stress granules are membrane-less cytoplasmic structures formed when translation initiation is inhibited during strong stress responses or viral infection[10,11]. They are composed of abundant messenger RNAs (mRNAs) stalled in translation initiation, RNA-binding proteins, and ribonucleoproteins. The abnormal regulation of stress granules contributes to neurodegeneration
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