title: Extended ubiquitin species are protein-based DUB inhibitors.
abstract: A frameshift mutation in the transcript of the ubiquitin-B gene leads to a C-terminally extended ubiquitin (Ub), UBB(+1). UBB(+1) has been considered to inhibit proteasomes and as such to be the underlying cause for toxic protein buildup correlated with certain neuropathological conditions. We demonstrate that expression of extended Ub variants leads to accumulation of heterogeneously linked polyubiquitin conjugates, indicating a pervasive effect on Ub-dependent turnover. 20S proteasomes selectively proteolyzed Ub extensions, yet no evidence for inhibition of 26S holoenzymes was found. However, among susceptible targets for inhibition was Ubp6, the primary enzyme responsible for disassembly of Lys48 linkages at 26S proteasomes. Processing of Lys48 and Lys63 linkages by other deubiquitinating enzymes (DUBs) was also inhibited. Disruption of Ub-dependent degradation by extended Ub variants may therefore be attributed to their inhibitory effect on select DUBs, thus shifting research efforts related to protein accumulation in neurodegenerative processes from proteasomes to DUBs.
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Daria
authors.initials: D
authors.lastname: Krutauz
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Reis
authors.affiliation: 1] Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel. [2] Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Nakasone
authors.affiliation: Department of Chemistry, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Peter
authors.initials: P
authors.lastname: Siman
authors.affiliation: Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland, USA.
authors.forename: Daoning
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Chemistry, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Brik
authors.affiliation: Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fushman
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Glickman
mesh_terms: D000595:Amino Acid Sequence; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008969:Molecular Sequence Data; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D007976:Leupeptins; D061988:Proteasome Inhibitors; D029701:Saccharomyces cerevisiae Proteins; C479419:UBB protein, human; D025801:Ubiquitin; D025821:Polyubiquitin; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C109028:UBP6 protein, S cerevisiae; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde