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 the Drosophila wing. 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.

中文翻译：

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调节平面细胞极性蛋白Frizzled-6从内质网输出的分子机制。


平面细胞极性（PCP）是细胞沿着上皮平面极化的过程，并受到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递送至质膜，在那里发挥其生理功能。然而，调节 PCP 蛋白转运的分子机制仍不清楚。在这里，我们发现 PCP 蛋白 Frizzled-6 向细胞表面的递送受到两个保守的多元基序的调节：一个位于其第一个细胞内环，另一个位于其 C 端胞质结构域。我们观察到卷曲的多元基序对于其在果蝇翅膀中的表面定位也很重要。机制分析结果表明，Frizzled-6 在内质网 (ER) 处包装成囊泡是通过多元基序与分泌相关 Ras 相关 GTPase 1A 上的 Glu-62 和 Glu-63 残基之间的直接相互作用来调节的(SAR1A) 外壳蛋白复合物 II (COPII) 亚基。此外，我们发现新合成的 Frizzled-6 在分泌转运途径中与另一种 PCP 蛋白钙粘蛋白 EGF LAG 七通道 G 型受体 1 (CELSR1) 相关，并且这种关联调节它们的表面递送。我们的结果揭示了对调节 Frizzled-6 ER 输出的分子机制的见解。他们还表明，CELSR1 与 Frizzled-6 的关联很重要，能够将 Frizzled-6 有效递送至细胞表面，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。