Rinschen, Markus M., Harder, Jennifer L., Carter-Timofte, Madalina E., Rodriguez, Luis Zanon, Mirabelli, Carmen, Demir, Fatih ORCID: 0000-0002-5744-0205, Kurmasheva, Naziia ORCID: 0000-0002-9609-5811, Ramakrishnan, Suresh K., Kunke, Madlen, Tan, Yifan, Billing, Anja, Dahlke, Eileen, Larionov, Alexey A., Bechtel-Walz, Wibke, Aukschun, Ute, Grabbe, Marlen, Nielsen, Rikke, Christensen, Erik I., Kretzler, Matthias, Huber, Tobias B., Wobus, Christiane E., Olagnier, David ORCID: 0000-0001-6912-0674, Siuzdak, Gary, Grahammer, Florian and Theilig, Franziska (2022). VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. Sci. Signal., 15 (762). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1937-9145

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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 beta-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harder, Jennifer L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter-Timofte, Madalina E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez, Luis ZanonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mirabelli, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demir, FatihUNSPECIFIEDorcid.org/0000-0002-5744-0205UNSPECIFIED
Kurmasheva, NaziiaUNSPECIFIEDorcid.org/0000-0002-9609-5811UNSPECIFIED
Ramakrishnan, Suresh K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunke, MadlenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, YifanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Billing, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahlke, EileenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larionov, Alexey A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bechtel-Walz, WibkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aukschun, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grabbe, MarlenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, RikkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christensen, Erik I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kretzler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, Tobias B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wobus, Christiane E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olagnier, DavidUNSPECIFIEDorcid.org/0000-0001-6912-0674UNSPECIFIED
Siuzdak, GaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grahammer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Theilig, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-690969
DOI: 10.1126/scisignal.abo7940
Journal or Publication Title: Sci. Signal.
Volume: 15
Number: 762
Date: 2022
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1937-9145
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AMINO-ACID TRANSPORTERS; PATHWAY; GALECTIN-3; INHIBITOR; MTOR; PHOSPHOPROTEOMICS; EMPAGLIFLOZIN; VISUALIZATION; ENDOCYTOSIS; TRAFFICKINGMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69096

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