A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly

Cell. 1999 Mar 5;96(5):635-44. doi: 10.1016/s0092-8674(00)80574-7.


Proteins modified by multiubiquitin chains are the preferred substrates of the proteasome. Ubiquitination involves a ubiquitin-activating enzyme, E1, a ubiquitin-conjugating enzyme, E2, and often a substrate-specific ubiquitin-protein ligase, E3. Here we show that efficient multiubiquitination needed for proteasomal targeting of a model substrate requires an additional conjugation factor, named E4. This protein, previously known as UFD2 in yeast, binds to the ubiquitin moieties of preformed conjugates and catalyzes ubiquitin chain assembly in conjunction with E1, E2, and E3. Intriguingly, E4 defines a novel protein family that includes two human members and the regulatory protein NOSA from Dictyostelium required for fruiting body development. In yeast, E4 activity is linked to cell survival under stress conditions, indicating that eukaryotes utilize E4-dependent proteolysis pathways for multiple cellular functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases
  • Biopolymers / metabolism
  • Cell Cycle Proteins / physiology
  • Cell Survival
  • Cell-Free System
  • Cloning, Molecular
  • Cysteine Endopeptidases
  • Fungal Proteins / genetics
  • Fungal Proteins / isolation & purification
  • Fungal Proteins / physiology*
  • Humans
  • Macromolecular Substances
  • Multienzyme Complexes
  • Multigene Family
  • Proteasome Endopeptidase Complex
  • Protein Processing, Post-Translational
  • Proteins / metabolism
  • Recombinant Fusion Proteins / physiology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae Proteins*
  • Stress, Physiological / metabolism
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitins / metabolism*
  • Valosin Containing Protein


  • Biopolymers
  • Cell Cycle Proteins
  • Fungal Proteins
  • Macromolecular Substances
  • Multienzyme Complexes
  • Proteins
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae Proteins
  • Ubiquitins
  • Ubiquitin-Conjugating Enzymes
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • CDC48 protein, S cerevisiae
  • Valosin Containing Protein
  • UFD2 protein, S cerevisiae