HIF2α Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5

The mammalian target of rapamycin (mTOR) pathway, which is essential for cell proliferation, is repressed in certain cell types in hypoxia. However, hypoxia-inducible factor 2 alpha (HIF2 alpha) can act as a proliferation-promoting factor in some biological settings. This paradoxical situation led us to study whether HIF2 alpha has a specific effect on mTORC1 regulation. Here we show that activation of the HIF2 alpha pathway increases mTORC1 activity by upregulating expression of the amino acid carrier SLC7A5. At the molecular level we also show that HIF2 alpha binds to the Slc7a5 proximal promoter. Our findings identify a link between the oxygen-sensing HIF2 alpha pathway and mTORC1 regulation, revealing the molecular basis of the tumor-promoting properties of HIF2 alpha in von Hippel-Lindau-deficient cells. We also describe relevant physiological scenarios, including those that occur in liver and lung tissue, wherein HIF2 alpha or low-oxygen tension drive mTORC1 activity and SLC7A5 expression.