LAUSR

The lipid kinase VPS34 orchestrates autophagy, endocytosis, and metabolism and is implicated in cancer and metabolic disease. The proximal tubule in the kidney is a key metabolic organ that controls reabsorption of nutrients such as fatty acids, amino acids, sugars, and proteins. Here, by combining metabolomics, proteomics, and phosphoproteomics analyses with functional and superresolution imaging assays of mice with an inducible deficiency in proximal tubular cells, we revealed that VPS34 controlled the metabolome of the proximal tubule. In addition to inhibiting pinocytosis and autophagy, VPS34 depletion induced membrane exocytosis and reduced the abundance of the retromer complex necessary for proper membrane recycling and lipid retention, leading to a loss of fuel and biomass. Integration of omics data into a kidney cell metabolomic model demonstrated that VPS34 deficiency increased β-oxidation, reduced gluconeogenesis, and enhanced the use of glutamine for energy consumption. Furthermore, the omics datasets revealed that VPS34 depletion triggered an antiviral response that included a decrease in the abundance of apically localized virus receptors such as ACE2. VPS34 inhibition abrogated SARS-CoV-2 infection in human kidney organoids and cultured proximal tubule cells in a glutamine-dependent manner. Thus, our results demonstrate that VPS34 adjusts endocytosis, nutrient transport, autophagy, and antiviral responses in proximal tubule cells in the kidney. Description The lipid kinase VPS34 limits nutrient loss but enables viral entry in renal proximal tubule cells. A renal gatekeeper for nutrients and viruses The kidney filters the blood and retains nutrients through endocytosis and active transport in cells lining the proximal tubule. Rinschen et al. investigated how this process is regulated by VPS34, a lipid kinase involved in the vesicular trafficking and endocytic sorting of membrane proteins. Multiomics analyses showed that deficiency of VPS34 in proximal tubule cells in mice decreased the cell surface abundance of nutrient transporters, which was associated with increased urinary loss of lipids and proteins. In addition, the cell surface abundance of viral entry receptors such as ACE2 was reduced. Accordingly, treatment with a VPS34 inhibitor attenuated SARS-CoV-2 entry in cultured proximal tubular cells and human kidney organoids. Thus, VPS34 inhibition could be used to treat diseases in which limiting the retention of nutrients confers clinical benefit (such as kidney cancer or diabetes) or to block viral infection of the kidney.