CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion
CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion
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CREG1 与 Sec8 相互作用促进心肌分化和细胞间粘附
DOI：
10.1002/stem.2434
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发表时间：
2016-11-01
期刊：
影响因子：
5.2
通讯作者：
Han, Yanling
中科院分区：
文献类型：
--
作者：
Liu, Jie;Qi, Yanmei;Han, Yanling
了解致密心肌结构形成过程中细胞间相互作用的调节对于通过增强干细胞衍生的心肌细胞与受体心肌的整合来实现真正的心脏再生非常重要。在这项研究中，我们发现 E1A 刺激基因的细胞阻遏蛋白 1 (CREG1) 在胚胎和成人心脏中均高度表达。功能获得和丧失分析表明，CREG1 是小鼠胚胎干 (ES) 细胞分化为心肌细胞以及以细胞自主方式形成粘性心肌样结构所必需的。此外，CREG1 直接与外囊复合物的 Sec8 相互作用，后者将囊泡束缚在质膜上。 CREG1 敲除 ES 细胞的定点诱变和拯救表明，CREG1 与 Sec8 结合是心肌细胞分化和凝聚所必需的。从机制上讲，CREG1、Sec8 和 N-钙粘蛋白在体内共定位于闰盘，并在培养的心肌细胞的细胞-细胞连接处富集。 CREG1 过表达增强粘附和间隙连接的组装。相比之下，它的敲除会抑制 Sec8-N-钙粘蛋白相互作用并诱导其降解。这些结果表明 CREG1 与 Sec8 的结合增强了细胞间连接的组装并促进心肌生成。
Understanding the regulation of cell-cell interactions during the formation of compact myocardial structures is important for achieving true cardiac regeneration through enhancing the integration of stem cell-derived cardiomyocytes into the recipient myocardium. In this study, we found that cellular repressor of E1A-stimulated genes 1 (CREG1) is highly expressed in both embryonic and adult hearts. Gain-and loss-of-function analyses demonstrated that CREG1 is required for differentiation of mouse embryonic stem (ES) cell into cardiomyocytes and the formation of cohesive myocardium-like structures in a cell-autonomous fashion. Furthermore, CREG1 directly interacts with Sec8 of the exocyst complex, which tethers vesicles to the plasma membrane. Site-directed mutagenesis and rescue of CREG1 knockout ES cells showed that CREG1 binding to Sec8 is required for cardiomyocyte differentiation and cohesion. Mechanistically, CREG1, Sec8, and N-cadherin colocalize at intercalated discs in vivo and are enriched at cell-cell junctions in cultured cardiomyocytes. CREG1 overexpression enhances the assembly of adherens and gap junctions. By contrast, its knockout inhibits the Sec8-N-cadherin interaction and induces their degradation. These results suggest that the CREG1 binding to Sec8 enhances the assembly of intercellular junctions and promotes cardiomyogenesis.