mTORC1 Activity is Required to Maintain Canonical Endocytic Recycling Pathway against Lysosomal Delivery [Metabolism]

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 mTORC1, a master metabolic sensor. Upon mTORC1 inactivation, either by starvation or by inhibitors, plasma membrane lipids and recycling receptors, such as sphingomyelin and transferrin receptors, are delivered to the lysosomes. This lysosomal targeting is independent of canonical autophagy: both wt and in Atg5-/- MEFs responded similary. Furthermore, we identify Hrs, an 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 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.

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