mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery
mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery
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DOI：
10.1074/jbc.m116.771451
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发表时间：
2017-04-07
影响因子：
4.8
通讯作者：
Zha, Xiaohui
中科院分区：
文献类型：
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作者：
Dauner, Kristin;Eid, Walaa;Zha, Xiaohui
哺乳动物细胞的质膜经历结构性内吞作用、内吞分选和循环，将营养物质输送到溶酶体。受体和膜脂一起，通常被返回到质膜以维持这种作用。然而，这一过程是否受到新陈代谢条件的影响尚不清楚。在此，我们报道内吞循环需要雷帕霉素的主动机械靶点(又名哺乳动物雷帕霉素靶点)(MTORC1)，它是一种主要的代谢感受器。当mTORC1被饥饿或抑制剂灭活时，循环受体和质膜脂类，如转铁蛋白受体和鞘磷脂，被输送到溶酶体。这种溶酶体靶向性不依赖于典型的自噬：WT和ATG5(-/-)小鼠胚胎成纤维细胞的反应相似。此外，我们确定肝细胞生长因子调节的酪氨酸激酶底物(HRS)，一种转运所需的内体分选复合体(护送-0)，作为mTORC1的下游靶标。HRS需要mTORC1的活性来维持其蛋白表达水平。在不降低mTORC1活性的情况下沉默hRs足以将转铁蛋白和鞘磷脂靶向溶酶体。因此，很明显，典型的循环途径受mTORC1的调节，可能最主要的是在mTORC1高度活跃的增殖细胞中。
The plasma membrane of mammalian cells undergoes constitutive endocytosis, endocytic sorting, and recycling, which delivers nutrients to the lysosomes. The receptors, along with membrane lipids, are normally returned to the plasma membrane to sustain this action. It is not known, however, whether this process is influenced by metabolic conditions. Here we report that endocytic recycling requires active mechanistic target of rapamycin (aka mammalian target of rapamycin) (mTORC1), a master metabolic sensor. Upon mTORC1 inactivation, either by starvation or by inhibitor, recycling receptors and plasma membrane lipids, such as transferrin receptors and sphingomyelin, are delivered to the lysosomes. This lysosomal targeting is independent of canonical autophagy: both WT and Atg5(-/-) mouse embryonic fibroblasts responded similarly. Furthermore, we identify hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), an endosomal sorting complexes required for transport (ESCORT-0) component, as a downstream target of mTORC1. Hrs requires mTORC1 activity to maintain its protein expression level. Silencing Hrs without decreasing mTORC1 activity is sufficient to target transferrin and sphingomyelin to the lysosomes. It is thus evident that the canonical recycling pathway is under the regulation of mTORC1 and likely most predominant in proliferating cells where mTORC1 is highly active.