An oxygen-adaptive interaction between SNHG12 and occludin maintains blood-brain barrier integrity
An oxygen-adaptive interaction between SNHG12 and occludin maintains blood-brain barrier integrity
复制标题
SNHG12 和 occludin 之间的氧适应性相互作用可维持血脑屏障的完整性
DOI：
10.1016/j.celrep.2022.110656
复制
发表时间：
2022-04-13
期刊：
影响因子：
8.8
通讯作者：
Chen, Yu-Hua
中科院分区：
文献类型：
--
作者：
Li, Yuan;Wei, Jia-Yi;Chen, Yu-Hua
脑微血管内皮细胞（BMECs）的紧密连接（TJs）在维持血脑屏障（BBB）完整性中起关键作用；然而，TJs在生理和病理刺激下的稳定性的精确调控仍然是难以捉摸的。在这里，利用RNA免疫沉淀与下一代测序（RIP-seq）和功能表征，我们发现SNHG12，一种长链非编码RNA (lncRNA)，通过直接与TJ蛋白occludin相互作用，对于维持血脑屏障的完整性至关重要。SNHG12与occludin的相互作用是氧适应性的，可以阻断Itch （E3泛素连接酶）介导的人bmec中occludin的泛素化和降解。小鼠内皮细胞Snhg12基因消融导致闭塞蛋白减少和血脑屏障泄漏，并显著加重缺氧诱导的血脑屏障破坏。缺氧对血脑屏障的不良影响可通过外源性SNHG12在脑内皮的过表达来缓解。总之，我们确定了一个直接TJ调节剂lncRNA SNHG12，它对血脑屏障完整性维持和氧适应至关重要。
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.