E4BP4 interacts with PERK to form a feedback loop mediating cold-induced female reproductive disorders.
Miao Yumeng, Ding Mengnan, Lu Yarong, Liu Zhihui, Wang Hongli, Chen Mingyue, Liu Kun, Wen Qing, Xing Chen, Huang Xin, Liu Guangchao, Ma Junguo, Song Lun
Abstract
In our previous report, PERK/NRF2/CX43/StAR/progesterone pathway activation in ovarian granulosa cells was shown to mediate cold-induced female reproductive disorders. However, how PERK is activated by low temperature remained unclear. In the present study, we found that the circadian protein E4BP4 was significantly upregulated in ovarian granulosa cells following exposure to cold or isoproterenol (ISO), a non-selective β-adrenergic receptor agonist that pharmacologically activates β-adrenergic signaling, a key component of the cold stress response. Mechanistically, E4BP4 interacted with PERK and was required for PERK activation and subsequent NRF2/CX43/StAR signaling, leading to increased progesterone secretion. Interestingly, NRF2 also acted as a transcriptional activator of E4BP4 under ISO treatment, and blocking PERK or NRF2 expression attenuated ISO-induced E4BP4 accumulation, suggesting a positive feedback loop involving PERK/NRF2/E4BP4. Collectively, these findings identify E4BP4 as a cold-responsive circadian protein that interacts with PERK and may contribute to cold-induced reproductive disorders via a bidirectional E4BP4-PERK feedback loop.
Key Findings
- E4BP4 is significantly upregulated in ovarian granulosa cells in response to cold or β-adrenergic signaling activation.
- E4BP4 interacts with PERK and is necessary for PERK activation and subsequent NRF2/CX43/StAR signaling, leading to increased progesterone secretion.
- A positive feedback loop exists between PERK, NRF2, and E4BP4 that mediates cold-induced female reproductive disorders.
Clinical Significance
Understanding the E4BP4-PERK-NRF2 feedback loop provides insights into the molecular mechanisms underlying cold-induced female reproductive disorders, potentially guiding therapeutic strategies to mitigate reproductive dysfunction caused by environmental stress.
Citation
Miao Yumeng, Ding Mengnan, Lu Yaronget al.. E4BP4 interacts with PERK to form a feedback loop mediating cold-induced female reproductive disorders. Cell stress & chaperones. 2026-Sep-05.