ABCG2 shields against epilepsy, relieves oxidative stress and apoptosis via inhibiting the ISGylation of STAT1 and mTOR

• Published in: Redox biology 2024-09, Vol.75, p.103262, Article 103262
• Main Authors: Li, Chang, Cai, Yi, Chen, Yongmin, Tong, Jingyi, Li, Youbin, Liu, Dong, Wang, Yun, Li, Zhiping, Wang, Yan, Li, Qifu
• Format: Article
• Language: English
• Subjects: ABCG2; Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Disease Models, Animal; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Humans; ISGylation; Kainic Acid; Male; Mice; Mice, Knockout; Microglia - metabolism; Neurons - metabolism; Neurons - pathology; Oxidative Stress; Signal Transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2024.103262

The transporter protein ABC subfamily G member 2 (ABCG2) is implicated in epilepsy; however, its specific role remains unclear. In this study, we assessed changes in ABCG2 expression and its role in epilepsy both in vitro and in vivo. We observed an instantaneous increase in ABCG2 expression in epileptic animals and cells. Further, ABCG2 overexpression significantly suppressed the oxidative stress and apoptosis induced by glutamate, kainic acid (KA), and lipopolysaccharide (LPS) in neuronal and microglia cells. Furthermore, inhibiting ABCG2 activity offset this protective effect. ABCG2-deficient mice (ABCG2−/−) showed shorter survival times and decreased survival rates when administered with pentylenetetrazole (PTZ). We also noticed the accumulation of signal transducer and activator of transcription 1 (STAT1) and decreased phosphorylation of mammalian target of rapamycin kinase (mTOR) along with increased ISGylation in ABCG2−/− mice. ABCG2 overexpression directly interacted with STAT1 and mTOR, leading to a decrease in their ISGylation. Our findings indicate the rapid increase in ABCG2 expression acts as a shield in epileptogenesis, indicating ABCG2 may serve as a potential therapeutic target for epilepsy treatment. Graphic abstract schematic summary of the ABCG2 effects on epilepsy. Evidence of in vivo and in vitro indicates that instantly increase of ABCG2 shields against epilepsy via inhibiting oxidative stress and apoptosis of neuron and microglia. Overexpression of ABCG2 directly combines with STAT1 and mTOR to induces phosphorylation of STAT1 and mTOR. On the contrary, deficiency of ABCG2 induced ISGylation of STAT1 and mTOR to inhibit their phosphorylation. [Display omitted]