An oxygen-adaptive interaction between SNHG12 and occludin maintains blood-brain barrier integrity

• Published in: Cell reports (Cambridge) 2022-04, Vol.39 (2), p.110656-110656, Article 110656
• Main Authors: Li, Yuan, Wei, Jia-Yi, Liu, Hui, Wang, Kang-Ji, Jin, Sheng-Nan, Su, Zheng-Kang, Wang, Hui-Jie, Shi, Jun-Xiu, Li, Bo, Shang, De-Shu, Fang, Wen-Gang, Qin, Xiao-Xue, Zhao, Wei-Dong, Chen, Yu-Hua
• Format: Article
• Language: English
• Subjects: Animals; blood-brain barrier; Blood-Brain Barrier - metabolism; Endothelial Cells - metabolism; endothelium; hypoxia; Hypoxia - metabolism; Mice; Occludin - metabolism; Occludin - pharmacology; Oxygen - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; tight junction; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110656

Tight junctions (TJs) of brain microvascular endothelial cells (BMECs) play a pivotal role in maintaining the blood-brain barrier (BBB) integrity; however, precise regulation of TJs stability in response to physiological and pathological stimuli remains elusive. Here, using RNA immunoprecipitation with next-generation sequencing (RIP-seq) and functional characterization, we identify SNHG12, a long non-coding RNA (lncRNA), as being critical for maintaining the BBB integrity by directly interacting with TJ protein occludin. The interaction between SNHG12 and occludin is oxygen adaptive and could block Itch (an E3 ubiquitin ligase)-mediated ubiquitination and degradation of occludin in human BMECs. Genetic ablation of endothelial Snhg12 in mice results in occludin reduction and BBB leakage and significantly aggravates hypoxia-induced BBB disruption. The detrimental effects of hypoxia on BBB could be alleviated by exogenous SNHG12 overexpression in brain endothelium. Together, we identify a direct TJ modulator lncRNA SNHG12 that is critical for the BBB integrity maintenance and oxygen adaption. [Display omitted] •lncRNA SNHG12 is critical for maintaining the blood-brain barrier (BBB) integrity•Oxygen levels regulate SNHG12 interaction with occludin to maintain BBB integrity•Endothelium Snhg12 knockout aggravates hypoxia-induced occludin degradation in mice•Endothelium SNHG12 overexpression alleviates hypoxia-induced BBB disruption in mice Li et al. identify an oxygen-adaptive interaction between lncRNA SNHG12 and the tight junction protein occludin in brain microvascular endothelial cells. This interaction stabilizes occludin by blocking its degradation by the ubiquitin-proteasome system and is critical for the blood-brain barrier integrity maintenance and oxygen adaption.