Yeast SREBP cleavage activation requires the Golgi Dsc E3 ligase complex

Mol Cell. 2011 Apr 22;42(2):160-71. doi: 10.1016/j.molcel.2011.02.035.

Abstract

Mammalian lipid homeostasis requires proteolytic activation of membrane-bound sterol regulatory element binding protein (SREBP) transcription factors through sequential action of the Golgi Site-1 and Site-2 proteases. Here we report that while SREBP function is conserved in fungi, fission yeast employs a different mechanism for SREBP cleavage. Using genetics and biochemistry, we identified four genes defective for SREBP cleavage, dsc1-4, encoding components of a transmembrane Golgi E3 ligase complex with structural homology to the Hrd1 E3 ligase complex involved in endoplasmic reticulum-associated degradation. The Dsc complex binds SREBP and cleavage requires components of the ubiquitin-proteasome pathway: the E2-conjugating enzyme Ubc4, the Dsc1 RING E3 ligase, and the proteasome. dsc mutants display conserved aggravating genetic interactions with components of the multivesicular body pathway in fission yeast and budding yeast, which lacks SREBP. Together, these data suggest that the Golgi Dsc E3 ligase complex functions in a post-ER pathway for protein degradation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Endopeptidases / metabolism
  • Golgi Apparatus / enzymology*
  • Multiprotein Complexes
  • Proprotein Convertases / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Processing, Post-Translational
  • Schizosaccharomyces / enzymology*
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Serine Endopeptidases / metabolism
  • Sterol Regulatory Element Binding Proteins / genetics
  • Sterol Regulatory Element Binding Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Cell Cycle Proteins
  • DSC1 protein, S pombe
  • Multiprotein Complexes
  • Schizosaccharomyces pombe Proteins
  • Sre1 protein, S pombe
  • Sterol Regulatory Element Binding Proteins
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • Endopeptidases
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1
  • Proteasome Endopeptidase Complex
  • SREBP site 2 protease