Dsc E3 ligase localization to the Golgi requires the ATPase Cdc48 and cofactor Ufd1 for activation of sterol regulatory element-binding protein in fission yeast

J Biol Chem. 2017 Sep 29;292(39):16333-16350. doi: 10.1074/jbc.M117.802025. Epub 2017 Aug 18.


Sterol regulatory element-binding proteins (SREBPs) in the fission yeast Schizosaccharomyces pombe regulate lipid homeostasis and the hypoxic response under conditions of low sterol or oxygen availability. SREBPs are cleaved in the Golgi through the combined action of the Dsc E3 ligase complex, the rhomboid protease Rbd2, and the essential ATPases associated with diverse cellular activities (AAA+) ATPase Cdc48. The soluble SREBP N-terminal transcription factor domain is then released into the cytosol to enter the nucleus and regulate gene expression. Previously, we reported that Cdc48 binding to Rbd2 is required for Rbd2-mediated SREBP cleavage. Here, using affinity chromatography and mass spectrometry experiments, we identified Cdc48-binding proteins in S. pombe, generating a list of many previously unknown potential Cdc48-binding partners. We show that the established Cdc48 cofactor Ufd1 is required for SREBP cleavage but does not interact with the Cdc48-Rbd2 complex. Cdc48-Ufd1 is instead required at a step prior to Rbd2 function, during Golgi localization of the Dsc E3 ligase complex. Together, these findings demonstrate that two distinct Cdc48 complexes, Cdc48-Ufd1 and Cdc48-Rbd2, are required for SREBP activation and low-oxygen adaptation in S. pombe.

Keywords: ATPases associated with diverse cellular activities (AAA); Cdc48; E3 ubiquitin ligase; SREBP; Schizosaccharomyces pombe; VCP; hypoxia; membrane transport; p97; transcription regulation.

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Gene Deletion
  • Glycosylation
  • Golgi Apparatus / enzymology
  • Golgi Apparatus / metabolism*
  • Immunoprecipitation
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Hydrolases / chemistry
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Protein Transport
  • Recombinant Fusion Proteins / metabolism
  • Schizosaccharomyces / enzymology
  • Schizosaccharomyces / metabolism*
  • Schizosaccharomyces pombe Proteins / chemistry
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Valosin Containing Protein


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carrier Proteins
  • Cell Cycle Proteins
  • DSC1 protein, S pombe
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Schizosaccharomyces pombe Proteins
  • Sre1 protein, S pombe
  • Sre2 protein, S pombe
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors
  • Ufd1 protein, S pombe
  • Dsc1 E3 ligase, S pombe
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Rbd2 protein, S pombe
  • Adenosine Triphosphatases
  • Valosin Containing Protein