University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Mol Cell Biol. 2022 Jul 14;14(3). doi: 10.1093/jmcb/mjac017.
The nuclear envelope comprises the outer nuclear membrane, inner nuclear membrane (INM), and nucleopore. Although ∼60 INM proteins have been identified, only a few of them have been well characterized, revealing their crucial roles. Our group focused on the INM protein transmembrane protein 201 (TMEM201), whose role in cellular function remains to be defined. In this study, we investigated the role of TMEM201 in endothelial cell migration and angiogenesis. Depletion of TMEM201 expression by short hairpin RNA-mediated interference impeded human umbilical vein endothelial cell (HUVEC) angiogenic behavior in tube formation and fibrin gel bead sprouting assays. Meanwhile, TMEM201-deficient HUVECs exhibited impaired migration ability. We next explored the underlying mechanism and found that the N-terminal of TMEM201 interacted with the linker of nucleoskeleton and cytoskeleton complex and was required for regulating endothelial cell migration and angiogenesis. These in vitro findings were further confirmed by using in vivo models. In Tmem201-knockout mice, retinal vessel development was arrested and aortic ring sprouting was defective. In addition, loss of tmem201 impaired zebrafish intersegmental vessel development. In summary, TMEM201 was shown to regulate endothelial cell migration and control the process of angiogenesis. This study is the first to reveal the role of INM proteins in the vascular system and angiogenesis.
核膜由外核膜、内核膜（INM）和核孔组成。虽然已经鉴定出约 60 种 INM 蛋白，但只有少数几种得到了很好的表征，揭示了它们的关键作用。我们的研究小组专注于 INM 蛋白跨膜蛋白 201（TMEM201），其在细胞功能中的作用仍有待确定。在这项研究中，我们研究了 TMEM201 在血管内皮细胞迁移和血管生成中的作用。通过短发夹 RNA 介导的干扰敲低 TMEM201 的表达，抑制了人脐静脉内皮细胞（HUVEC）在管形成和纤维蛋白凝胶珠发芽测定中的血管生成行为。同时，TMEM201 缺陷的 HUVEC 表现出迁移能力受损。我们接下来探索了潜在的机制，发现 TMEM201 的 N 端与核骨架和细胞骨架复合物的连接子相互作用，并且对于调节内皮细胞迁移和血管生成是必需的。这些体外发现进一步通过体内模型得到了证实。在 Tmem201 敲除小鼠中，视网膜血管发育被阻断，主动脉环发芽受损。此外，tmem201 的缺失会损害斑马鱼节间血管的发育。总之，TMEM201 被证明可以调节内皮细胞迁移并控制血管生成过程。这项研究首次揭示了 INM 蛋白在血管系统和血管生成中的作用。
