Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins

Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12753-8. doi: 10.1073/pnas.162488899. Epub 2002 Sep 19.

Abstract

This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. The sequences of human insig-1 and -2 are 59% identical. Both proteins are predicted to contain six transmembrane helices. The proteins differ functionally in two respects: (i) production of insig-1, but not insig-2, in cultured mammalian cells requires nuclear SREBPs; and (ii) at high levels of expression, insig-1, but not insig-2, can block SCAP movement in the absence of exogenous sterols. The combined actions of insig-1 and -2 permit feedback regulation of cholesterol synthesis over a wide range of sterol concentrations.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Northern
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • CHO Cells
  • Carrier Proteins / chemistry*
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Cholesterol / metabolism
  • Cricetinae
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / metabolism*
  • Golgi Apparatus / metabolism
  • Humans
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins*
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology*
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Plasmids / metabolism
  • Precipitin Tests
  • Promoter Regions, Genetic
  • Protein Binding
  • Proteins / metabolism*
  • Proteins / physiology*
  • Sequence Homology, Amino Acid
  • Sterol Regulatory Element Binding Protein 1
  • Time Factors
  • Transcription Factors*
  • Transfection

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • DNA, Complementary
  • DNA-Binding Proteins
  • INSIG2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proteins
  • SREBF1 protein, human
  • SREBP cleavage-activating protein
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Cholesterol

Associated data

  • GENBANK/AF527626
  • GENBANK/AF527627
  • GENBANK/AF527628
  • GENBANK/AF527629
  • GENBANK/AF527630
  • GENBANK/AF527631
  • GENBANK/AF527632
  • GENBANK/AY112745