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VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. 2022
Markus M Rinschen, and
Jennifer L Harder, and
Madalina E Carter-Timofte, and
Luis Zanon Rodriguez, and
Carmen Mirabelli, and
Fatih Demir, and
Naziia Kurmasheva, and
Suresh K Ramakrishnan, and
Madlen Kunke, and
Yifan Tan, and
Anja Billing, and
Eileen Dahlke, and
Alexey A Larionov, and
Wibke Bechtel-Walz, and
Ute Aukschun, and
Marlen Grabbe, and
Rikke Nielsen, and
Erik I Christensen, and
Matthias Kretzler, and
Tobias B Huber, and
Christiane E Wobus, and
David Olagnier, and
Gary Siuzdak, and
Florian Grahammer, and
Franziska Theilig
Scripps Center for Metabolomics, Scripps Research, La Jolla, CA 92037, USA.
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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