title: Enzymatic blockade of the ubiquitin-proteasome pathway.
abstract: Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrates, a treatment less toxic than the use of proteasome inhibitors. Recognition of misfolded proteins in the ER lumen, their dislocation to the cytosol, and degradation are usually tightly coupled but can be uncoupled by the EBV-DUB: a misfolded glycoprotein that originates in the ER accumulates in association with cytosolic chaperones as a deglycosylated intermediate. Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ernst
authors.forename: Jasper H L
authors.initials: JH
authors.lastname: Claessen
authors.forename: Britta
authors.initials: B
authors.lastname: Mueller
authors.forename: Sumana
authors.initials: S
authors.lastname: Sanyal
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Annemarthe G
authors.initials: AG
authors.lastname: van der Veen
authors.forename: Oktay
authors.initials: O
authors.lastname: Kirak
authors.forename: Christian D
authors.initials: CD
authors.lastname: Schlieker
authors.forename: Wilhelm A
authors.initials: WA
authors.lastname: Weihofen
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D055162:Biocatalysis; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000201:enzymology*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D018832:Molecular Chaperones; D025801:Ubiquitin; D014764:Viral Proteins; D046988:Proteasome Endopeptidase Complex