Molecular mechanisms that regulate export of the planar cell-polarity protein Frizzled-6 out of the endoplasmic reticulum
Molecular mechanisms that regulate export of the planar cell-polarity protein Frizzled-6 out of the endoplasmic reticulum
复制标题
调节平面细胞极性蛋白Frizzled-6从内质网输出的分子机制
DOI：
10.1074/jbc.ra120.012835
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发表时间：
2020-07-03
影响因子：
4.8
通讯作者：
Guo, Yusong
中科院分区：
文献类型：
--
作者：
Tang, Xiao;Zhang, Lina;Guo, Yusong
平面细胞极性（PCP）是细胞沿上皮平面沿着极化的过程，受几种跨膜信号蛋白的调节。合成后，这些PCP蛋白沿着分泌转运途径被递送至质膜，在质膜上它们执行其生理功能。然而，调节PCP蛋白质转运的分子机制在很大程度上仍不清楚。在这里，我们发现，PCP蛋白，卷曲-6，到细胞表面的交付是由两个保守的多碱基基序：一个位于其第一个胞内环和其他在其C-末端胞质结构域。我们观察到Frizzled的多元基序对于其在果蝇翅中的表面定位也是重要的。从一个机制分析的结果表明，卷曲-6包装成囊泡在内质网（ER）是由一个直接的相互作用之间的多元基序和Glu-62和Glu-63残基的分泌相关的Ras相关的GTd 1A（SAR 1A）的外壳蛋白复合物II（COPII）的亚基。此外，我们发现，新合成的卷曲-6与另一种PCP蛋白，钙粘蛋白EGF LAG七通G型受体1（CELSR 1），在分泌运输途径，这种协会调节其表面交付。我们的研究结果揭示了对调控卷曲蛋白-6 ER出口的分子机制的见解。他们还表明，CELSR 1与Frizzled-6的关联是重要的，能够有效地将Frizzled-6递送到细胞表面，提供质量控制机制，确保这两种PCP蛋白在细胞边界的适当化学计量。
Planar cell polarity (PCP) is a process during which cells are polarized along the plane of the epithelium and is regulated by several transmembrane signaling proteins. After their synthesis, these PCP proteins are delivered along the secretory transport pathway to the plasma membrane, where they perform their physiological functions. However, the molecular mechanisms that regulate PCP protein transport remain largely unclear. Here, we found that the delivery of a PCP protein, Frizzled-6, to the cell surface is regulated by two conserved polybasic motifs: one located in its first intracellular loop and the other in its C-terminal cytosolic domain. We observed that the polybasic motif of Frizzled is also important for its surface localization in theDrosophilawing. Results from a mechanistic analysis indicated that Frizzled-6 packaging into vesicles at the endoplasmic reticulum (ER) is regulated by a direct interaction between the polybasic motif and the Glu-62 and Glu-63 residues on the secretion-associated Ras-related GTPase 1A (SAR1A) subunit of coat protein complex II (COPII). Moreover, we found that newly synthesized Frizzled-6 is associated with another PCP protein, cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1), in the secretory transport pathway, and that this association regulates their surface delivery. Our results reveal insights into the molecular machinery that regulates the ER export of Frizzled-6. They also suggest that the association of CELSR1 with Frizzled-6 is important, enabling efficient Frizzled-6 delivery to the cell surface, providing a quality control mechanism that ensures the appropriate stoichiometry of these two PCP proteins at cell boundaries.