O-GlcNAc modification is an endogenous inhibitor of the proteasome

Cell. 2003 Dec 12;115(6):715-25. doi: 10.1016/s0092-8674(03)00974-7.


The ubiquitin proteasome system classically selects its substrates for degradation by tagging them with ubiquitin. Here, we describe another means of controlling proteasome function in a global manner. The 26S proteasome can be inhibited by modification with the enzyme, O-GlcNAc transferase (OGT). This reversible modification of the proteasome inhibits the proteolysis of the transcription factor Sp1 and a hydrophobic peptide through inhibition of the ATPase activity of 26S proteasomes. The Rpt2 ATPase in the mammalian proteasome 19S cap is modified by O-GlcNAc in vitro and in vivo and as its modification increases, proteasome function decreases. This mechanism may couple proteasomes to the general metabolic state of the cell. The O-GlcNAc modification of proteasomes may allow the organism to respond to its metabolic needs by controlling the availability of amino acids and regulatory proteins.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Amino Acids / metabolism
  • Animals
  • Cell Line
  • Cysteine Endopeptidases / metabolism*
  • Energy Metabolism / physiology
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • N-Acetylglucosaminyltransferases / metabolism*
  • Peptides / metabolism
  • Proteasome Endopeptidase Complex
  • Proteins / metabolism*
  • RNA, Small Interfering / pharmacology
  • Rats
  • Sp1 Transcription Factor / metabolism
  • Ubiquitins / metabolism*


  • Amino Acids
  • Multienzyme Complexes
  • Peptides
  • Proteins
  • RNA, Small Interfering
  • Sp1 Transcription Factor
  • Ubiquitins
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases