Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi.
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.
DeBose-Boyd
R A
RA
Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas 75390-9046, USA.
Brown
M S
MS
Li
W P
WP
Nohturfft
A
A
Goldstein
J L
JL
Espenshade
P J
PJ
D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000378:metabolism*; D018257:Helix-Loop-Helix Motifs; D006868:Hydrolysis; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D016350:Leucine Zippers; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors; D020126:Brefeldin A; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1