Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome

Nature. 1997 Feb 20;385(6618):737-40. doi: 10.1038/385737a0.


In eukaryotes, ubiquitin (Ub)-dependent proteolysis is essential for bulk protein turnover as well as diverse processes including cell-cycle control, differentiation, antigen presentation, and the stress response. Generally, multiple ubiquitins are added onto a substrate to form an isopeptide-linked 'polyubiquitin' chain, which targets substrates for degradation by the 26S proteasome. The specificity of Ub-dependent degradation was thought to depend primarily on the selection of targets for ubiquitination, but recently we have reported evidence for a second level of specificity in which (poly)Ub-protein conjugates are partitioned among two fates: degradation of the protein substrate by the 26S proteasome; and disassembly by Ub isopeptidase(s) to regenerate the protein substrate. Potentially, an isopeptidase could influence degradation by 'editing' (poly)Ub-protein conjugates according to the extent of ubiquitination rather than the structure of the ubiquitination target itself. Here we describe a bovine isopeptidase that is well suited to such an editing function because of its unique localization and specificity. This enzyme is an intrinsic subunit of PA700, the 19S regulatory complex of the 26S proteasome. By disassembling the degradation signal from only the distal end of (poly)Ub chains, this isopeptidase can selectively rescue poorly ubiquitinated or slowly degraded Ub-protein conjugates from proteolysis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biopolymers / metabolism
  • Carbon-Nitrogen Lyases*
  • Cattle
  • Lyases / metabolism*
  • Peptide Hydrolases / metabolism*
  • Polyubiquitin
  • Proteasome Endopeptidase Complex*
  • Proteins / metabolism
  • Substrate Specificity
  • Ubiquitins / metabolism*


  • Biopolymers
  • PA700 proteasome activator
  • Proteins
  • Ubiquitins
  • Polyubiquitin
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Lyases
  • Carbon-Nitrogen Lyases
  • isopeptidase