Hsp90 Mediates Membrane Deformation and Exosome Release

• Published in: Molecular cell Vol. 71; no. 5; pp. 689 - 702.e9
• Main Authors: Lauwers, Elsa, Wang, Yu-Chun, Gallardo, Rodrigo, Van der Kant, Rob, Michiels, Emiel, Swerts, Jef, Baatsen, Pieter, Zaiter, Samantha S., McAlpine, Shelli R., Gounko, Natalia V., Rousseau, Frederic, Schymkowitz, Joost, Verstreken, Patrik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-09-2018
• Subjects: chaperone; exosome; Hsp90; membrane remodeling; multivesicular body; Hsp90; membrane remodeling; chaperone; exosome; multivesicular body
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.07.016

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.
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•Hsp90 has a previously unrecognized membrane-remodeling function•This novel activity occurs via an evolutionarily conserved amphipathic helix•Compounds that lock the Hsp90 dimer in a closed state inhibit membrane deformation•Hsp90 membrane-deforming ability promotes exosome release in vitro and in vivo
Hsp90 is a master regulator of protein homeostasis. Lauwers et al. now find that Hsp90 directly binds and deforms membranes in addition to operating as chaperone. This novel activity of Hsp90 promotes the fusion of multivesicular bodies with the plasma membrane and the subsequent release of exosomes.