Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi

Cell. 1999 Dec 23;99(7):703-12. doi: 10.1016/s0092-8674(00)81668-2.

Abstract

Cholesterol homeostasis in animal cells is achieved by regulated cleavage of membrane-bound transcription factors, designated SREBPs. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein, SCAP, which forms a complex with SREBPs. In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi, where SREBPs are cleaved by Site-1 protease (S1P). Sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviates the SCAP requirement and renders cleavage insensitive to sterols. Transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.

Publication types

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

MeSH terms

  • Animals
  • Brefeldin A / pharmacology
  • CCAAT-Enhancer-Binding Proteins*
  • CHO Cells
  • Cricetinae
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Fluorescent Antibody Technique
  • Golgi Apparatus / metabolism*
  • Helix-Loop-Helix Motifs
  • Hydrolysis
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins
  • Leucine Zippers
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Proprotein Convertases*
  • Serine Endopeptidases / metabolism*
  • Sterol Regulatory Element Binding Protein 1
  • Sterols / pharmacology
  • Transcription Factors / metabolism*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 1
  • Sterols
  • Transcription Factors
  • Brefeldin A
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1