SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless.
SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless.
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SNX3 通过调节 Wntless 的逆转录酶依赖性回收来控制 Wingless/Wnt 分泌
作者：
果蝇 Wingless (Wg) 在发育过程中充当形态发生素。 Wg 分泌由七次跨膜货物 Wntless (Wls) 控制。我们最近确定了 Retromer 是参与 WLS 贩运的关键监管者。由于分选连接蛋白 (SNX) 分子是逆转录酶复合物的重要组成部分，我们假设逆转录酶介导的 Wnt 分泌需要特定的 SNX。在这里，我们为所有 8 个 snx 成员生成了果蝇突变体，并将果蝇 SNX3 (DSNX3) 鉴定为 Wg 分泌所需的必需分子。我们发现翼盘中 Dsnx3 突变克隆的 Wg 分泌及其信号活性存在缺陷。 Dsnx3 耗尽的 S2 细胞培养基中的 Wg 水平也显着降低。重要的是，Dsnx3突变细胞中的Wls水平显着降低，并且Wls的过度表达可以挽救Dsnx3突变细胞中观察到的Wg分泌缺陷。此外，DSNX3 可以与逆转录酶成分 Vps35 相互作用，并与早期内涵体中的 Vps35 共定位。这些数据表明 DSNX3 通过依赖逆转录酶的 Wls 回收来调节 Wg 分泌。相比之下，我们发现果蝇 snx1 和 snx6（经典逆转录复合物的两个组成部分）的突变细胞中 Wg 分泌没有缺陷。 DSNX1 或 DSNX6 的异位表达无法挽救 Dsnx3 突变翼盘和 Dsnx3 dsRNA 处理的 S2 细胞中的 Wg 分泌缺陷。这些数据证明了 DSNX3-retromer 复合物在 Wls 回收中的特异性。总之，我们的研究结果表明 DSNX3 作为逆转录酶的货物特异性成分，是 Wls 和 Wg/Wnt 分泌的内吞再循环所必需的。
Drosophila Wingless (Wg) acts as a morphogen during development. Wg secretion is controlled by a seven-pass transmembrane cargo Wntless (Wls). We have recently identified retromer as a key regulator involved in Wls trafficking. As sorting nexin (SNX) molecules are essential components of the retromer complex, we hypothesized that specific SNX (s) is required for retromer-mediated Wnt secretion. Here, we generated Drosophila mutants for all of the eight snx members, and identified Drosophila SNX3 (DSNX3) as an essential molecule required for Wg secretion. We show that Wg secretion and its signaling activity are defective in Dsnx3 mutant clones in wing discs. Wg levels in the culture medium of Dsnx3-depleted S2 cells are also markedly reduced. Importantly, Wls levels are strikingly reduced in Dsnx3 mutant cells, and overexpression of Wls can rescue the Wg secretion defect observed in Dsnx3 mutant cells. Moreover, DSNX3 can interact with the retromer component Vps35, and co-localize with Vps35 in early endosomes. These data indicate that DSNX3 regulates Wg secretion via retromer-dependent Wls recycling. In contrast, we found that Wg secretion is not defective in cells mutant for Drosophila snx1 and snx6, two components of the classical retromer complex. Ectopic expression of DSNX1 or DSNX6 fails to rescue the Wg secretion defect in Dsnx3 mutant wing discs and in Dsnx3 dsRNA-treated S2 cells. These data demonstrate the specificity of the DSNX3-retromer complex in Wls recycling. Together, our findings suggest that DSNX3 acts as a cargo-specific component of retromer, which is required for endocytic recycling of Wls and Wg/Wnt secretion.
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DOI：
10.1042/bss0720223
发表时间：
2005-01-01
期刊：
LIPIDS, RAFTS AND TRAFFIC
影响因子：
--
作者：
Gallop, JL;McMahon, HT
通讯作者：
McMahon, HT
DOI：
10.1073/pnas.0535280100
发表时间：
2003-03-04
影响因子：
11.1
作者：
Gong, WJ;Golic, KG
通讯作者：
Golic, KG
DOI：
10.1073/pnas.0409558102
发表时间：
2005-10-18
影响因子：
11.1
作者：
Griffin, CT;Trejo, J;Magnuson, T
通讯作者：
Magnuson, T
影响因子：
4
作者：
Korolchuk, Viktor I.;Schuetz, Martin M.;O'Kane, Cahir J.
通讯作者：
O'Kane, Cahir J.
影响因子：
64.5
作者：
Nolo, R;Abbott, LA;Bellen, HJ
通讯作者：
Bellen, HJ