Novel Chemical Tool for Understanding Membrane Remodeling in the Cell
Published:09 Aug.2024 Source:Umea University
In a study published in PNAS, Umeå researchers describe a natural product-like molecule, Tantalosin, that inhibits interaction between two proteins in complexes that reshape membranes inside the cell. The findings lead to a deeper understanding of how membrane remodelling works in human cells and future development of new drugs. Their study is a good case to use small molecules as valuable chemical tools for understanding complex biological mechanisms. Membranes of cells are made of lipids and proteins, and they serve barrier functions for cells and intracellular organelles. Membranes of cells are highly dynamic mosaic-fluid structures that undergo constant reshaping. The endosomal sorting complex required for transport (ESCRT) is tasked with remodelling membranes inside the cell. The ESCRT machinery assembles at the site in the cell where membranes need deformation and then forms helical protein polymers that can contract and pinch off cell membranes.
Previously, Professor Yaowen Wu and his group, in collaboration with Professor Herbert Waldmann's laboratory at Max Planck Institute Dortmund in Germany, identified a chemical molecule, Tantalosin, that induces a phenotype like autophagy -- a self-eating process in the cell. They observed a very interesting phenomenon in the cell treated with Tantalosin and investigated further the molecular mechanism how Tantalosin works in the cell. "To our surprise, we found that none of the autophagy-related proteins were on the list of potential targets. However, IST1 protein in ESCRT complexes was identified and validated as the cellular target of Tantalosin. We were excited to work on deciphering this unexpected connection between ESCRT complexes and autophagy," says first author Anastasia Knyazeva, who just recently completed her doctoral degree at the Department of Chemistry at Umeå University.
Furthermore, the researchers looked inside the cell and found that Tantalosin rapidly disrupts the recycling of cell-surface receptors back to the cell surface. This property could be potentially beneficial for treating certain types of cancers that are driven by cell-surface receptors. In this study, the researchers found that LC3 protein, which is usually a hallmark of autophagy, is linked to the endosomal membranes during Tantalosin treatment. Interestingly, the canonical autophagic degradation was not observed. Instead, they found that the process follows a noncanonical autophagy pathway.