In a study published in the Proceedings of the National Academy of Sciences (PNAS), researchers from Umeå University have identified a natural product-like molecule called Tantalosin that inhibits interactions between proteins involved in reshaping cell membranes. This discovery sheds light on the mechanisms of membrane remodeling in human cells and could pave the way for the development of new drugs. The research, led by Professor Yaowen Wu, involved collaboration with colleagues in Umeå, Stockholm, and Germany.
Cell membranes, composed of lipids and proteins, play crucial roles in maintaining cell structure and function. The endosomal sorting complex required for transport (ESCRT) is responsible for reshaping membranes within cells. The ESCRT machinery forms helical protein polymers that contract and pinch off cell membranes at specific sites. The research team, in a previous study, had identified Tantalosin, a synthetic molecule inspired by alkaloids from the medical plant Cinchona, which induces a phenotype resembling autophagy – a process of self-eating in cells. They observed intriguing effects of Tantalosin on cells and sought to investigate its molecular mechanism further.
Through chemical proteomics analysis, the researchers discovered that Tantalosin targets the IST1 protein in ESCRT complexes, rather than autophagy-related proteins, as initially hypothesized. This unexpected connection between ESCRT complexes and autophagy sparked further investigation into the mechanism of action of Tantalosin. By using biochemical and cell biological methods, they found that Tantalosin inhibits the interaction between IST1 and its binding partner CHMP1B, disrupting the formation of ordered filaments of these proteins.
Further examination using a transmission electron microscope revealed that Tantalosin disrupts the formation of ordered IST1-CHMP1B filaments within cells. Moreover, the researchers observed that Tantalosin interferes with the recycling of cell-surface receptors back to the cell surface, which could have potential implications for treating certain types of cancers driven by cell-surface receptors. Additionally, during Tantalosin treatment, the researchers found a linkage between the LC3 protein and endosomal membranes, suggesting a noncanonical autophagy pathway in cells.
The researchers believe that Tantalosin represents a unique molecule that can shed light on new functions of LC3-membrane conjugation and its role in membrane deformation processes. Further studies are needed to elucidate the specific mechanisms underlying this noncanonical autophagic pathway. This study highlights the importance of small molecules as valuable tools for understanding complex biological mechanisms and opens up new possibilities for the development of novel therapeutic strategies targeting membrane remodeling processes in human cells.
