Impaired Cx43 gap junction endocytosis causes morphological and functional defects in zebrafish.
Impaired Cx43 gap junction endocytosis causes morphological and functional defects in zebrafish.
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DOI：
10.1091/mbc.e20-12-0797
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发表时间：
2021-10-01
影响因子：
3.3
通讯作者：
Falk MM
中科院分区：
文献类型：
--
作者：
Hyland C;Mfarej M;Hiotis G;Lancaster S;Novak N;Iovine MK;Falk MM
间隙连接通过形成物理耦合细胞的通道来介导直接的细胞间通讯，从而连接它们的细胞质，允许分子、离子和电脉冲的交换。间隙连接由连接蛋白 (Cx) 蛋白组装而成，其中连接蛋白 43 (Cx43) 表达最普遍，研究也最充分。虽然决定 Cx43 生命周期的分子事件已在很大程度上得到表征，但 Cxs 的半衰期异常短，仅为 1-5 小时，导致间隙连接通道的持续内吞作用和生物合成替代，这仍然令人费解。 Cx43 C 末端 (CT) 结构域作为蛋白质的调节中心，影响间隙连接功能的各个方面。在这里，Cx43 CT（氨基酸 256-289）（已知编码调节间隙连接周转的关键残基的区域）内的缺失被用于使用培养细胞（Cx43Δ256-289）和斑马鱼模型（cx43lh10）检查失调的 Cx43 间隙连接内吞作用的影响。我们报告这种 CT 缺失会导致间隙连接内吞作用缺陷以及间隙连接细胞间通讯增加。 cx43lh10 斑马鱼中 Cx43 蛋白含量增加，特别是在心脏组织中，间隙连接斑块更大，Cx43 蛋白半衰期更长，这些都与严重受损的发育相一致。我们的研究结果首次证明，连续的 Cx43 间隙连接内吞作用是间隙连接功能的一个重要方面，当受损时，会引起心血管发育和功能的重大生理问题。
Gap junctions mediate direct cell-to-cell communication by forming channels that physically couple cells, thereby linking their cytoplasm, permitting the exchange of molecules, ions, and electrical impulses. Gap junctions are assembled from connexin (Cx) proteins, with connexin 43 (Cx43) being the most ubiquitously expressed and best studied. While the molecular events that dictate the Cx43 life cycle have largely been characterized, the unusually short half-life of Cxs of only 1–5 h, resulting in constant endocytosis and biosynthetic replacement of gap junction channels, has remained puzzling. The Cx43 C-terminal (CT) domain serves as the regulatory hub of the protein affecting all aspects of gap junction function. Here, deletion within the Cx43 CT (amino acids 256–289), a region known to encode key residues regulating gap junction turnover, is employed to examine the effects of dysregulated Cx43 gap junction endocytosis using cultured cells (Cx43∆256-289) and a zebrafish model (cx43lh10). We report that this CT deletion causes defective gap junction endocytosis as well as increased gap junction intercellular communication. Increased Cx43 protein content in cx43lh10 zebrafish, specifically in the cardiac tissue, larger gap junction plaques, and longer Cx43 protein half-lives coincide with severely impaired development. Our findings demonstrate for the first time that continuous Cx43 gap junction endocytosis is an essential aspect of gap junction function and, when impaired, gives rise to significant physiological problems as revealed here for cardiovascular development and function.
影响因子：
3.5
作者：
Gerhart SV;Jefferis R;Iovine MK
通讯作者：
Iovine MK
影响因子：
3.7
作者：
Gerhart SV;Eble DM;Burger RM;Oline SN;Vacaru A;Sadler KC;Jefferis R;Iovine MK
通讯作者：
Iovine MK