Caspase-mediated proteolysis of the sorting nexin 2 disrupts retromer assembly and potentiates Met/hepatocyte growth factor receptor signaling.
Caspase-mediated proteolysis of the sorting nexin 2 disrupts retromer assembly and potentiates Met/hepatocyte growth factor receptor signaling.
复制标题
caspase介导的分选nexin 2的蛋白水解破坏了逆转录组装和增强型/肝细胞生长因子受体信号传导。
DOI：
10.1038/cddiscovery.2016.100
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发表时间：
2017
影响因子：
7
通讯作者：
Denault JB
中科院分区：
文献类型：
--
作者：
Duclos CM;Champagne A;Carrier JC;Saucier C;Lavoie CL;Denault JB
细胞凋亡的展开涉及半胱氨酰肽酶的半胱天冬酶家族对数百种蛋白质的裂解。这些底物中包括参与细胞内囊泡运输的蛋白质，其最终结果是关闭控制蛋白质运输到细胞器和质膜的关键过程。然而，由于受体运输和信号传导相互交织，特定蛋白质的裂解可能会导致意想不到的后果。在这里，我们表明，在细胞凋亡中，分选 nexin 1 和 2（SNX1 和 SNX2）（参与内体分选的两种蛋白质）被起始 caspase 裂解，在 SNX2 的情况下也被执行 caspase-6 裂解。此外，SNX1 在多个位点被切割，包括随后的谷氨酸残基。 SNX2 的裂解导致与内体到反高尔基体网络转运蛋白 Vps35 的关联丧失，并导致其相关伙伴 Vps26 与其内体离域。我们还证明，SNX2 耗竭会导致细胞中肝细胞生长因子受体酪氨酸磷酸化和 Erk1/2 信号传导增加。最后，我们发现结直肠癌中 SNX2 mRNA 和蛋白质水平降低，并且 SNX2 基因表达降低与癌症患者死亡率增加相关。我们的研究揭示了表征特定死亡底物的半胱天冬酶产生的切割片段的重要性，因为它们在生理（信号/运输）途径的调节机制或导致发病机制的功能障碍中具有潜在意义。
The unfolding of apoptosis involves the cleavage of hundreds of proteins by the caspase family of cysteinyl peptidases. Among those substrates are proteins involved in intracellular vesicle trafficking with a net outcome of shutting down the crucial processes governing protein transport to organelles and to the plasma membrane. However, because of the intertwining of receptor trafficking and signaling, cleavage of specific proteins may lead to unintended consequences. Here we show that in apoptosis, sorting nexin 1 and 2 (SNX1 and SNX2), two proteins involved in endosomal sorting, are cleaved by initiator caspases and also by executioner caspase-6 in the case of SNX2. Moreover, SNX1 is cleaved at multiple sites, including following glutamate residues. Cleavage of SNX2 results in a loss of association with the endosome-to-trans-Golgi network transport protein Vps35 and in a delocalization from endosomes of its associated partner Vps26. We also demonstrate that SNX2 depletion causes an increase in hepatocyte growth factor receptor tyrosine phosphorylation and Erk1/2 signaling in cells. Finally, we show that SNX2 mRNA and protein levels are decreased in colorectal carcinoma and that lower SNX2 gene expression correlates with an increase in cancer patient mortality. Our study reveals the importance to characterize the cleavage fragments produced by caspases of specific death substrates given their potential implication in the mechanism of regulation of physiological (signaling/trafficking) pathways or in the dysfunction leading to pathogenesis.