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

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VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. / Rinschen, Markus M; Harder, Jennifer L; Carter-Timofte, Madalina E; Zanon Rodriguez, Luis; Mirabelli, Carmen; Demir, Fatih; Kurmasheva, Naziia; 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; Siuzdak, Gary; Grahammer, Florian; Theilig, Franziska.

In: SCIENCE SIGNALING, Vol. 15, No. 762, 29.11.2022, p. eabo7940.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Rinschen, MM, Harder, JL, Carter-Timofte, ME, Zanon Rodriguez, L, Mirabelli, C, Demir, F, Kurmasheva, N, Ramakrishnan, SK, Kunke, M, Tan, Y, Billing, A, Dahlke, E, Larionov, AA, Bechtel-Walz, W, Aukschun, U, Grabbe, M, Nielsen, R, Christensen, EI, Kretzler, M, Huber, TB, Wobus, CE, Olagnier, D, Siuzdak, G, Grahammer, F & Theilig, F 2022, 'VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney', SCIENCE SIGNALING, vol. 15, no. 762, pp. eabo7940. https://doi.org/10.1126/scisignal.abo7940

APA

Rinschen, M. M., Harder, J. L., Carter-Timofte, M. E., Zanon Rodriguez, L., Mirabelli, C., Demir, F., Kurmasheva, N., Ramakrishnan, S. K., Kunke, M., Tan, Y., Billing, A., Dahlke, E., Larionov, A. A., Bechtel-Walz, W., Aukschun, U., Grabbe, M., Nielsen, R., Christensen, E. I., Kretzler, M., ... Theilig, F. (2022). VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. SCIENCE SIGNALING, 15(762), eabo7940. https://doi.org/10.1126/scisignal.abo7940

Vancouver

Rinschen MM, Harder JL, Carter-Timofte ME, Zanon Rodriguez L, Mirabelli C, Demir F et al. VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. SCIENCE SIGNALING. 2022 Nov 29;15(762):eabo7940. https://doi.org/10.1126/scisignal.abo7940

Bibtex

@article{de94b5d15827452899ee9afe79dbc9ec,
title = "VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney",
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.",
keywords = "Humans, Animals, Mice, Glutamine, COVID-19, SARS-CoV-2, Kidney, Nutrients, Antiviral Agents, Lipids",
author = "Rinschen, {Markus M} and Harder, {Jennifer L} and Carter-Timofte, {Madalina E} and {Zanon Rodriguez}, Luis and Carmen Mirabelli and Fatih Demir and Naziia Kurmasheva and Ramakrishnan, {Suresh K} and Madlen Kunke and Yifan Tan and Anja Billing and Eileen Dahlke and Larionov, {Alexey A} and Wibke Bechtel-Walz and Ute Aukschun and Marlen Grabbe and Rikke Nielsen and Christensen, {Erik I} and Matthias Kretzler and Huber, {Tobias B} and Wobus, {Christiane E} and David Olagnier and Gary Siuzdak and Florian Grahammer and Franziska Theilig",
year = "2022",
month = nov,
day = "29",
doi = "10.1126/scisignal.abo7940",
language = "English",
volume = "15",
pages = "eabo7940",
journal = "SCI SIGNAL",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "762",

}

RIS

TY - JOUR

T1 - VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney

AU - Rinschen, Markus M

AU - Harder, Jennifer L

AU - Carter-Timofte, Madalina E

AU - Zanon Rodriguez, Luis

AU - Mirabelli, Carmen

AU - Demir, Fatih

AU - Kurmasheva, Naziia

AU - Ramakrishnan, Suresh K

AU - Kunke, Madlen

AU - Tan, Yifan

AU - Billing, Anja

AU - Dahlke, Eileen

AU - Larionov, Alexey A

AU - Bechtel-Walz, Wibke

AU - Aukschun, Ute

AU - Grabbe, Marlen

AU - Nielsen, Rikke

AU - Christensen, Erik I

AU - Kretzler, Matthias

AU - Huber, Tobias B

AU - Wobus, Christiane E

AU - Olagnier, David

AU - Siuzdak, Gary

AU - Grahammer, Florian

AU - Theilig, Franziska

PY - 2022/11/29

Y1 - 2022/11/29

N2 - 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.

AB - 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.

KW - Humans

KW - Animals

KW - Mice

KW - Glutamine

KW - COVID-19

KW - SARS-CoV-2

KW - Kidney

KW - Nutrients

KW - Antiviral Agents

KW - Lipids

U2 - 10.1126/scisignal.abo7940

DO - 10.1126/scisignal.abo7940

M3 - SCORING: Journal article

C2 - 36445937

VL - 15

SP - eabo7940

JO - SCI SIGNAL

JF - SCI SIGNAL

SN - 1945-0877

IS - 762

ER -