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首页> 外文期刊>Molecular and Cellular Biology >TPC1 Has Two Variant Isoforms, and Their Removal Has Different Effects on Endo-Lysosomal Functions Compared to Loss of TPC2
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TPC1 Has Two Variant Isoforms, and Their Removal Has Different Effects on Endo-Lysosomal Functions Compared to Loss of TPC2

机译：TPC1有两种变异同工型，与TPC2缺失相比，去除它们对内-溶酶体功能的影响不同

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Organelle ion homeostasis within the endo-lysosomal system is critical for physiological functions. Two-pore channels (TPCs) are cation channels that reside in endo-lysosomal organelles, and overexpression results in endo-lysosomal trafficking defects. However, the impact of a lack of TPC expression on endo-lysosomal trafficking is unknown. Here, we characterize Tpcn1 expression in two transgenic mouse lines (Tpcn1XG716 and Tpcn1T159) and show expression of a novel evolutionarily conserved Tpcn1B transcript from an alternative promoter, raising important questions regarding the status of Tpcn1 expression in mice recently described to be Tpcn1 knockouts. We show that the transgenic Tpcn1T159 line lacks expression of both Tpcn1 isoforms in all tissues analyzed. Using mouse embryonic fibroblasts (MEFs) from Tpcn1?/? and Tpcn2?/? animals, we show that a lack of Tpcn1 or Tpcn2 expression has no significant impact on resting endo-lysosomal pH or morphology. However, differential effects in endo-lysosomal function were observed upon the loss of Tpcn1 or Tpcn2 expression; thus, while Tpcn1?/? MEFs have impaired trafficking of cholera toxin from the plasma membrane to the Golgi apparatus, Tpcn2?/? MEFs show slower kinetics of ligand-induced platelet-derived growth factor receptor β (PDGFRβ) degradation, which is dependent on trafficking to lysosomes. Our findings indicate that TPC1 and TPC2 have important but distinct roles in the endo-lysosomal pathway.
机译：溶酶体系统内的细胞器离子稳态对于生理功能至关重要。两孔通道（TPC）是驻留在溶酶体细胞器中的阳离子通道，过表达会导致溶酶体运输缺陷。但是，缺乏TPC表达对溶酶体运输的影响尚不清楚。在这里，我们表征了两种转基因小鼠品系（ Tpcn1 XG716 和 Tpcn1 T159 中的 Tpcn1 表达的特征sup>）并显示了来自另一启动子的新型进化上保守的 Tpcn1B 转录本的表达，这引发了有关 Tpcn1 表达在最近描述为的小鼠中的状态的重要问题Tpcn1 淘汰赛。我们显示，转基因的 Tpcn1 T159 品系在所有分析的组织中均缺乏两种 Tpcn1 同工型的表达。使用来自 Tpcn1 ？/？和 Tpcn2 ？/？动物的小鼠胚胎成纤维细胞（MEF），我们发现 Tpcn1 或 Tpcn2 表达的缺乏对静止的溶酶体pH或形态没有显着影响。然而，在 Tpcn1 或 Tpcn2 表达缺失时，观察到了溶酶体功能的差异。因此，尽管 Tpcn1 ？/？ MEF损害了霍乱毒素从质膜向高尔基体的运输，但 Tpcn2 ？/ α MEFs表现出较慢的配体诱导的血小板衍生生长因子受体β（PDGFRβ）降解动力学，这取决于向溶酶体的运输。我们的发现表明，TPC1和TPC2在溶酶体途径中具有重要但截然不同的作用。

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