From the Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, France (A. Métais, I.L., A. Melet, S.U.-J., R.P., A.V., A.G.d.P., A.S., O.B.-S., P.G.L., C.M.-L.); CNRS UMR8601, Université Paris Descartes, France (A. Melet); and Aix Marseille Univ, INSERM, MMG, France (S.S., S.Z.).
Circ Res. 2018 Mar 16;122(6):e34-e48. doi: 10.1161/CIRCRESAHA.117.312015. Epub 2018 Jan 26.
Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that regulate actin cytoskeleton remodeling during cardiac cell differentiation.
The Asb2α (Ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2) CRL5 (cullin 5 RING E3 ubiquitin ligase) triggers polyubiquitylation and subsequent degradation by the proteasome of FLNs (filamins). Here, we investigate the role of Asb2α in heart development and its mechanisms of action.
Using knockout embryos, we show that is an essential gene, critical to heart morphogenesis and function, although its loss does not interfere with the overall patterning of the embryonic heart tube. We show that the Asb2α E3 ubiquitin ligase controls Flna stability in immature cardiomyocytes. Importantly, Asb2α-mediated degradation of the actin-binding protein Flna marks a previously unrecognized intermediate step in cardiac cell differentiation characterized by cell shape changes and actin cytoskeleton remodeling. We further establish that in the absence of Asb2α, myofibrils are disorganized and that heartbeats are inefficient, leading to embryonic lethality in mice.
These findings identify Asb2α as an unsuspected key regulator of cardiac cell differentiation and shed light on the molecular and cellular mechanisms determining the onset of myocardial cell architecture and its link with early cardiac function. Although Flna is known to play roles in cytoskeleton organization and to be required for heart function, this study now reveals that its degradation mediated by Asb2α ensures essential functions in differentiating cardiac progenitors.
心脏发育涉及心脏祖细胞的分化和心肌细胞收缩肌节装置的组装。然而，对于调节心脏细胞分化过程中肌动蛋白细胞骨架重塑的机制知之甚少。
Asb2α（含锚蛋白重复序列和细胞因子信号抑制盒 2 的蛋白）CRL5（Cullin5 RING E3 泛素连接酶）触发 FLN（细丝蛋白）的多泛素化和随后的蛋白酶体降解。在这里，我们研究了 Asb2α 在心脏发育中的作用及其作用机制。
使用 敲除胚胎，我们表明 是一种必需基因，对心脏形态发生和功能至关重要，尽管其缺失不干扰胚胎心脏管的整体模式。我们表明，Asb2α E3 泛素连接酶控制未成熟心肌细胞中 Flna 的稳定性。重要的是，Asb2α 介导的肌动蛋白结合蛋白 Flna 的降解标志着心脏细胞分化的一个以前未被认识的中间步骤，其特征是细胞形状变化和肌动蛋白细胞骨架重塑。我们进一步确定，在缺乏 Asb2α 的情况下，肌原纤维排列紊乱，心跳效率低下，导致小鼠胚胎致死。
这些发现确定了 Asb2α 是心脏细胞分化的一个意想不到的关键调节剂，并揭示了决定心肌细胞结构的起始及其与早期心脏功能的关系的分子和细胞机制。虽然 Flna 已知在细胞骨架组织中发挥作用并且是心脏功能所必需的，但本研究现在揭示了其由 Asb2α 介导的降解确保了分化的心脏祖细胞的重要功能。
