While studying how renal filtration (endocytosis) is regulated for efficient nutrient uptake by a lipid kinase (VPS34) in mice, an international team of scientists discovered that inhibiting the lipase kinase could prevent a viral infection. The team published their research “VPS34-dependent control of proximal tubule cell apical membrane function and nutrient recovery by the kidney” in Science Signaling.
VPS 34 is involved in vesicular trafficking and endocytic sorting of membrane proteins. The team carried out a multiomic approach to the study which showed that lack of lipid kinase in proximal renal tubule cells in mice reduced the abundance of cell surface nutrient transporters, which was associated with increased urinary loss of lipids, amino acids, sugars and proteins. In addition, the number of viral entry receptors on the cell surface was reduced. Subsequently, treatment with a lipid kinase inhibitor reduced SARS-CoV-2 virus entry into cultured proximal tubular cells and human kidney organoids.
Guardian of viral infections
“…by combining metabolomics, proteomics, and phosphoproteomics analysis with super-resolution and functional imaging assays of mice with an inducible deficiency in proximal tubular cells, we revealed that VPS34 controlled the proximal tubule metabolome. In addition to inhibiting pinocytosis and autophagy, VPS34 depletion induced membrane exocytosis and reduced the abundance of the retromeric complex necessary for proper membrane recycling and lipid retention, leading to a loss of fuel and biomass.” the researchers write.
schematic summary. [Science Signaling: DOI: 10.1126/scisignal.abo7940]
“Integration of omics data into a renal cell metabolomic model demonstrated that VPS34 deficiency increased β-oxidation, reduced gluconeogenesis, and enhanced glutamine use for energy consumption. Furthermore, the omics data sets revealed that VPS34 depletion triggered an antiviral response that included a decrease in the abundance of apically located virus receptors such as ACE2. Inhibition of VPS34 abrogated SARS-CoV-2 infection in human kidney organoids and cultured proximal tubule cells in a glutamine-dependent manner. “Therefore, our results demonstrate that VPS34 adjusts endocytosis, nutrient transport, autophagy, and antiviral responses in proximal tubule cells in the kidney.
The study showed that lipid kinase blockade could be used to treat diseases where limiting nutrient retention provides clinical benefit, such as kidney cancer or diabetes, or to block a viral infection of the kidney.
“Our main goal in this study was to collect and organize new insights into the fundamental processes of cell physiology. Although this is hypothesized, these large-scale, comprehensive data sets can be critical to understanding medical problems. In this case, we ultimately improved targeted drug treatment, for example, for kidney-related diseases or infections,” said Markus Rinschen, MD, first author of the study and associate professor at the Aarhus Institute for Advanced Study and Department of Biomedicine. from Aarhus University. . “Of course, more knowledge needs to be collected before conclusions about human relevance can be drawn.”
The study involved a collaboration between researchers from Aarhus University, Hamburg Eppendorf University Hospital, the University of Kiel and the University of Michigan.
Source: news.google.com