Du William W, Qadir Javeria, Du Kevin Y, Chen Yu, Wu Nan, Yang Burton B
Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M4N3M5, Canada.
Adv Sci (Weinh). 2023 Oct;10(28):e2300425. doi: 10.1002/advs.202300425. Epub 2023 Aug 11.
Current studies on actin function primarily rely on cytoplasmic actin due to the absence of cellular models specifically expressing nuclear actin. Here, cell models capable of expressing varying levels of nuclear F/G-actin are generated and a significant role of nuclear actin in the regulation of epithelial-mesenchymal transition (EMT) is uncovered. Through immunoprecipitation and mass spectrometry analyses, distinct binding partners for nuclear F-actin (β-catenin, SMAD2, and SMAD3) and nuclear G-actin (MYBBP1A, NKRF, and MYPOP) are investigated, which respectively modulate EMT-promoting and EMT-repressing transcriptional events. While nuclear F-actin promotes EMT with enhanced cell migration, survival, and elongated mesenchymal morphology, nuclear G-actin represses EMT and related cell activities. Mechanistically, nuclear F-actin enhances β-catenin, SMAD2, and SMAD3 expression and stability in the nuclei, while nuclear G-actin increases MYBBP1A, NKRF, and MYPOP expression and stability in the nuclei. The association between nuclear F/G-actin and N-cadherin/E-cadherin in the cell lines (in vitro), and increased nuclear actin polymerization in the wound healing cells (in vivo) affirm a significant role of nuclear actin in EMT regulation. With evidence of nuclear actin polymerization and EMT during development, and irregularities in disease states such as cancer and fibrosis, targeting nuclear actin dynamics to trigger dysregulated EMT warrants ongoing study.
由于缺乏特异性表达核肌动蛋白的细胞模型，目前关于肌动蛋白功能的研究主要依赖于细胞质肌动蛋白。在此，我们构建了能够表达不同水平核F / G - 肌动蛋白的细胞模型，并揭示了核肌动蛋白在上皮 - 间质转化（EMT）调控中的重要作用。通过免疫沉淀和质谱分析，研究了核F - 肌动蛋白（β - 连环蛋白、SMAD2和SMAD3）和核G - 肌动蛋白（MYBBP1A、NKRF和MYPOP）的不同结合伙伴，它们分别调节促进EMT和抑制EMT的转录事件。核F - 肌动蛋白通过增强细胞迁移、存活和延长间质形态来促进EMT，而核G - 肌动蛋白则抑制EMT及相关细胞活动。从机制上讲，核F - 肌动蛋白增强细胞核中β - 连环蛋白、SMAD2和SMAD3的表达和稳定性，而核G - 肌动蛋白增加细胞核中MYBBP1A、NKRF和MYPOP的表达和稳定性。细胞系中（体外）核F / G - 肌动蛋白与N - 钙黏蛋白/E - 钙黏蛋白之间的关联，以及伤口愈合细胞中（体内）核肌动蛋白聚合增加，证实了核肌动蛋白在EMT调控中的重要作用。鉴于在发育过程中存在核肌动蛋白聚合和EMT的证据，以及在癌症和纤维化等疾病状态下出现的异常情况，针对核肌动蛋白动力学以触发失调的EMT的研究仍在进行中。
