影響因子：5.1

期刊：MOLECULAR NEUROBIOLOGY

作者列表：Liu Chao, Gao Qing, Dong Jian, Cai Hui

發(fā)表時(shí)間：2023-11-2

DOI:10.1007/s12035-023-03735-8

主要研究成果：Autophagy has been involved in protection of ischemia/reperfusion (I/R)-induced injury in many tissues including the brain. The upstream stimulatory factor 2 (Usf2) was proposed as a regulator in aging and degenerative brain diseases; however, the its role in autophagy during cerebral I/R injury remains unclear. Here, the middle cerebral artery occlusion (MCAO) operation was applied to establish an I/R mouse model. We showed that Usf2 was significantly upregulated in I/R-injured brain, accompanied by decreased levels of autophagy. Then, oxygen-glucose deprivation/recovery (OGD/R) treatment was used to establish a cellular I/R model in HT22 neurons, and lentiviral interference vector against Usf2 (LV-sh-Usf2) was used to infect the neurons. Our results showed that Usf2 was significantly upregulated in OGD/R-treated HT22 neurons that displayed an increased level in cell apoptosis and decreased levels in cell viability and autophagy, and interference of Usf2 largely rescued the effects of OGD/R on cell viability, apoptosis, and autophagy, suggesting an important role of Usf2 in neuron autophagy. In the mechanism exploration, we found that, as a transcription factor, Usf2 bound to the promoter of YTHDF1, a famous reader of N6-Methyladenosine (m6A), also induced by OGD/R, and promoted its transcription. Overexpression of YTHDF1 was able to reverse the improvement of Usf2 interference on viability and autophagy of HT22 neurons. Moreover, YTHDF1 suppressed autophagy to induce HT22 cell apoptosis through increasing m6A-mediated stability of Cdc25A, a newly identified autophagy inhibitor. Finally, we demonstrated that interference of Usf2 markedly improved autophagy and alleviated I/R-induced injury in MCAO mice.