Activation of a Membrane-Bound Transcription Factor by Regulated ubiquitin/proteasome-dependent Processing

Cell. 2000 Sep 1;102(5):577-86. doi: 10.1016/s0092-8674(00)00080-5.

Abstract

Processing of integral membrane proteins in order to liberate active proteins is of exquisite cellular importance. Examples are the processing events that govern sterol regulation, Notch signaling, the unfolded protein response, and APP fragmentation linked to Alzheimer's disease. In these cases, the proteins are thought to be processed by regulated intramembrane proteolysis, involving site-specific, membrane-localized proteases. Here we show that two homologous yeast transcription factors SPT23 and MGA2 are made as dormant ER/nuclear membrane-localized precursors and become activated by a completely different mechanism that involves ubiquitin/proteasome-dependent processing. SPT23 and MGA2 are relatives of mammalian NF-kappaB and control unsaturated fatty acid levels. Intriguingly, proteasome-dependent processing of SPT23 is regulated by fatty acid pools, suggesting that the precursor itself or interacting partners are sensors of membrane composition or fluidity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases
  • Cell Cycle Proteins / physiology
  • Cysteine Endopeptidases / metabolism*
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism
  • Endosomal Sorting Complexes Required for Transport
  • Fatty Acid Desaturases / genetics
  • Fatty Acids, Unsaturated / metabolism
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Gene Expression Regulation, Fungal*
  • Genes, Dominant / genetics
  • Intracellular Membranes / chemistry
  • Intracellular Membranes / metabolism*
  • Membrane Proteins
  • Microsomes / chemistry
  • Microsomes / metabolism
  • Models, Biological
  • Multienzyme Complexes / metabolism*
  • Mutation / genetics
  • NF-kappa B / metabolism
  • Nuclear Pore Complex Proteins*
  • Nuclear Proteins / physiology
  • Nucleocytoplasmic Transport Proteins
  • Promoter Regions, Genetic / genetics
  • Proteasome Endopeptidase Complex
  • Protein Precursors / metabolism
  • Protein Processing, Post-Translational*
  • Proteins / physiology
  • RNA, Fungal / analysis
  • RNA, Fungal / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins*
  • Stearoyl-CoA Desaturase
  • Trans-Activators*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligase Complexes*
  • Ubiquitins / metabolism*
  • Valosin Containing Protein

Substances

  • Cell Cycle Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Fatty Acids, Unsaturated
  • Fungal Proteins
  • MGA2 protein, S cerevisiae
  • Membrane Proteins
  • Multienzyme Complexes
  • NF-kappa B
  • NPL4 protein, S cerevisiae
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • Nucleocytoplasmic Transport Proteins
  • Protein Precursors
  • Proteins
  • RNA, Fungal
  • RNA, Messenger
  • SPT23 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Trans-Activators
  • Transcription Factors
  • Ubiquitins
  • Fatty Acid Desaturases
  • Stearoyl-CoA Desaturase
  • delta-9 fatty acid desaturase
  • Ubiquitin-Protein Ligase Complexes
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • CDC48 protein, S cerevisiae
  • Valosin Containing Protein
  • RSP5 protein, S cerevisiae