Hsp90 Mediates Membrane Deformation and Exosome Release

• DOI: 10.1016/j.molcel.2018.07.016
• Publication Date: 2018-09-06T14:44:24Z
• Authors: Elsa Lauwers; Yu-Chun Wang; Rodrigo Gallardo; Rob Van der Kant; Emiel Michiels; Jef Swerts; Pieter Baatsen; Samantha S. Zaiter; Shelli R. McAlpine; Natalia V. Gounko; Frederic Rousseau; Joost Schymkowitz; Patrik Verstreken
• Keywords: Male; Biochemistry & Molecular Biology; Protein Conformation; SHOCK-PROTEIN 90; Exosomes; SACCHAROMYCES-CEREVISIAE; TRANSSYNAPTIC TRANSMISSION; 03 medical and health sciences; Animals; MOLECULAR CHAPERONE HSP90; HSP90 Heat-Shock Proteins; 0303 health sciences; Science & Technology; Cell-Free System; Cell Membrane; EXTRACELLULAR VESICLES; MULTIVESICULAR BODIES; Multivesicular Bodies; CALCIUM-DEPENDENT MANNER; Cell Biology; STEROID-RECEPTOR; DROSOPHILA-MELANOGASTER; WEB SERVER; Drosophila; Female; Life Sciences & Biomedicine; Molecular Chaperones; Protein Binding

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.