Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Nat Commun. 2021 May 12;12(1):2736. doi: 10.1038/s41467-021-23047-6.
Endothelial barrier integrity is ensured by the stability of the adherens junction (AJ) complexes comprised of vascular endothelial (VE)-cadherin as well as accessory proteins such as β-catenin and p120-catenin. Disruption of the endothelial barrier due to disassembly of AJs results in tissue edema and the influx of inflammatory cells. Using three-dimensional structured illumination microscopy, we observe that the mitochondrial protein Mitofusin-2 (Mfn2) co-localizes at the plasma membrane with VE-cadherin and β-catenin in endothelial cells during homeostasis. Upon inflammatory stimulation, Mfn2 is sulfenylated, the Mfn2/β-catenin complex disassociates from the AJs and Mfn2 accumulates in the nucleus where Mfn2 negatively regulates the transcriptional activity of β-catenin. Endothelial-specific deletion of Mfn2 results in inflammatory activation, indicating an anti-inflammatory role of Mfn2 in vivo. Our results suggest that Mfn2 acts in a non-canonical manner to suppress the inflammatory response by stabilizing cell-cell adherens junctions and by binding to the transcriptional activator β-catenin.
内皮细胞屏障的完整性由黏着连接（AJ）复合物的稳定性来保证，这些复合物由血管内皮钙黏蛋白（VE-钙黏蛋白）以及β-连环蛋白和 p120-连环蛋白等辅助蛋白组成。由于 AJ 的解体导致内皮细胞屏障的破坏会导致组织水肿和炎症细胞的涌入。通过三维结构照明显微镜观察，我们发现在稳态条件下，线粒体蛋白线粒体融合蛋白 2（Mfn2）与 VE-钙黏蛋白和β-连环蛋白在血管内皮细胞的质膜上共定位。在炎症刺激下，Mfn2 发生磺化，Mfn2/β-连环蛋白复合物从 AJ 解离，Mfn2 积累在核内，在核内 Mfn2 负调控 β-连环蛋白的转录活性。内皮细胞特异性敲除 Mfn2 会导致炎症激活，这表明 Mfn2 在体内具有抗炎作用。我们的结果表明，Mfn2 通过稳定细胞-细胞黏附连接以及与转录激活因子β-连环蛋白结合，以非典型方式发挥抑制炎症反应的作用。
