VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney

Authors:

Markus M. Rinschen, Jennifer L. Harder, Madalina E. Carter-Timofte, Luis Zanon Rodriguez, Carmen Mirabelli, Fatih Demir, Naziia Kurmasheva, Suresh K. Ramakrishnan, Madlen Kunke, Yifan Tan, Anja Billing, Eileen Dahlke, Alexey A. Larionov, Wibke Bechtel-Walz, Ute Aukschun, Marlen Grabbe, Rikke Nielsen, Erik I. Christensen, Matthias Kretzler, Tobias B. Huber, Christiane E. Wobus, David Olagnier, Gary Siuzdak, Florian Grahammer, Franziska Theilig

Keywords:

Renal gatekeeper, SARS-CoV-2, Vesicle Trafficking

Abstract:

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.

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