title: Release of autoinhibition converts ESCRT-III components into potent inhibitors of HIV-1 budding.
abstract: The endosomal sorting complex ESCRT-III, which is formed by the structurally related CHMP proteins, is engaged by HIV-1 to promote viral budding. Here we show that progressive truncations into the C-terminal acidic domains of CHMP proteins trigger an increasingly robust anti-HIV budding activity. Together with biochemical evidence for specific intramolecular interactions between the basic and acidic halves of CHMP3 and CHMP4B, these results suggest that the acidic domains are autoinhibitory. The acidic half of CHMP3 also interacts with the endosome-associated ubiquitin isopeptidase AMSH, and the coexpression of AMSH or its CHMP3-binding domain converts wild-type CHMP3 into a potent inhibitor of HIV-1 release. Point mutations in CHMP3 that prevent binding to AMSH abrogate this effect, suggesting that binding to AMSH relieves the autoinhibition of CHMP3. Collectively, our results indicate that CHMP proteins are regulated through an autoinhibitory switch mechanism that allows tight control of ESCRT-III assembly.
authors.affiliation: Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Zamborlini
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Usami
authors.forename: Sheli R
authors.initials: SR
authors.lastname: Radoshitzky
authors.forename: Elena
authors.initials: E
authors.lastname: Popova
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palu
authors.forename: Heinrich
authors.initials: H
authors.lastname: Göttlinger
mesh_terms: D000143:Acids; D000998:Antiviral Agents / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000143:Acids; D000998:Antiviral Agents; C498543:CHMP3 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins