Involvement of circadian clock protein PER2 in controlling sleep deprivation induced HMGB1 up-regulation by targeting p300 in the cortex

作者：Min Zhang, Z. Ma, Haoran Cui, Yijie Miao, Yin Yu, Qing Wen, Zhihui Liu, Xin Huang, Chen Xing, Kun Liu, Hui Peng, Lun Song · 发表于：Scientific Reports · 年份：2025 · DOI：10.1038/s41598-025-96931-6 · 被引用次数：4 · 研究领域：Circadian rhythm and melatonin、Sleep and Wakefulness Research、Advanced Glycation End Products research

Lack of sleep is a common problem in current society, which can induce various brain dysfunctions. Neuroinflammation is a typical reaction caused by sleep deficit and is considered as a common basis for various neurological disorders and cognitive impairments, but the related mechanisms have not been fully clarified. The circadian clock protein plays a critical role in maintaining physiological homeostasis, including sleep/wake cycles. Circadian disorders induced by sleep deficit might contribute to the development of neuroinflammation. In the current study, we observed that sleep deprivation (SD) induced elevated expression of High-mobility group box 1 (HMGB1), one of the most important mediators of neuroinflammation, in the cortical microglia and cerebrospinal fluids. Moreover, acetylation-dependent nuclear export of HMGB1 was involved in up-regulation and secretion of HMGB1 after sleep deprivation. Further studies indicated that sleep deprivation induced an increase in the expression of acetyltransferase p300 and a decrease in the expression of deacetylase SIRT1, which synergistically enhanced the acetylation level of HMGB1 in the cortical microglial cells, thereby triggered the nuclear export and secretion of HMGB1. Most importantly, circadian clock protein PER2 constitutively interacted with p300 and inhibited its expression in the microglial cells, which can be interrupted by PER2 downregulation upon sleep deprivation, leading to the increased expression of p300 and ace...