Du William W, Zhou Chi, Yang Hui, Wen Shuoyang, Chen Yu, Chen Eric X, Yang Xiuwei H, Li Feiya, Du Kevin Y, Yuan Hui, Ye Ting, Qadir Javeria, Yang Burton B
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Research (Wash D C). 2024 Aug 23;7:0441. doi: 10.34133/research.0441. eCollection 2024.
Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention.
结肠炎是一种慢性肠道疾病，其特征是大肠内壁受损，确切的潜在病因仍未完全明确。在本研究中，我们提供证据表明环状RNA circNlgn在促进结肠炎发展中起关键作用。结肠炎患者产生的circNlgn水平显著更高。表达circNlgn的转基因小鼠对结肠炎的发展和进展表现出更高的易感性，这主要归因于circNlgn编码的蛋白质异构体Nlgn173的存在。Nlgn173易位进入细胞核，在那里它与肌动蛋白相互作用，阻碍肌动蛋白相关蛋白2和3（Arp2/3）复合物与肌动蛋白分子的结合。因此，这导致肌动蛋白聚合减少。从机制上讲，Nlgn173增强了核肌动蛋白酪氨酸-53位点的磷酸化，降低了其与Arp2/3复合物相互作用的能力，并导致丝状肌动蛋白水平下降。肌动蛋白动力学的这些改变导致结肠上皮细胞的细胞周期进程受到抑制、凋亡增加和增殖减少，从而加剧结肠炎的发展和进展。相反，circNlgn的沉默或对Nlgn173翻译和核易位的靶向抑制导致核肌动蛋白聚合增加、细胞存活率提高、凋亡减少，并最终改善体内结肠炎的结局。有趣的是，核肌动蛋白聚合与PIAS3的表达高度相关，PIAS3在结肠炎中调节信号转导和转录激活因子3以及NF-κB活性。诸如circNlgn敲低和靶向结肠上皮细胞核肌动蛋白聚合等策略可能为急性溃疡性结肠炎的临床干预探索一条新途径。
