Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, MOLECULAR CHAPERONE HSP90, CALCIUM-DEPENDENT MANNER, SHOCK-PROTEIN 90, SACCHAROMYCES-CEREVISIAE, TRANSSYNAPTIC TRANSMISSION, DROSOPHILA-MELANOGASTER, EXTRACELLULAR VESICLES, MULTIVESICULAR BODIES, STEROID-RECEPTOR, WEB SERVER, Hsp90, chaperone, exosome, membrane remodeling, multivesicular body, Animals, Cell Membrane, Cell-Free System, Drosophila, Exosomes, Female, HSP90 Heat-Shock Proteins, Male, Molecular Chaperones, Multivesicular Bodies, Protein Binding, Protein Conformation, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences, 42 Health sciences

Abstract:

Hsp90 is an essential chaperone that guards proteome integrity and amounts to 2% of cellular protein. We now find that Hsp90 also has the ability to directly interact with and deform membranes via an evolutionarily conserved amphipathic helix. Using a new cell-free system and in vivo measurements, we show this amphipathic helix allows exosome release by promoting the fusion of multivesicular bodies (MVBs) with the plasma membrane. We dissect the relationship between Hsp90 conformation and membrane-deforming function and show that mutations and drugs that stabilize the open Hsp90 dimer expose the helix and allow MVB fusion, while these effects are blocked by the closed state. Hence, we structurally separated the Hsp90 membrane-deforming function from its well-characterized chaperone activity, and we show that this previously unrecognized function is required for exosome release.