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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Brefeldin A / pharmacology
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CCAAT-Enhancer-Binding Proteins*
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CHO Cells
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Cricetinae
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DNA-Binding Proteins / metabolism*
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Endoplasmic Reticulum / metabolism*
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Fluorescent Antibody Technique
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Golgi Apparatus / metabolism*
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Helix-Loop-Helix Motifs
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Hydrolysis
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Immunoblotting
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Intracellular Signaling Peptides and Proteins
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Leucine Zippers
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Membrane Proteins / deficiency
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Membrane Proteins / metabolism*
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Nuclear Proteins / metabolism*
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Proprotein Convertases*
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Serine Endopeptidases / metabolism*
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Sterol Regulatory Element Binding Protein 1
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Sterols / pharmacology
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Transcription Factors / metabolism*
Substances
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CCAAT-Enhancer-Binding Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nuclear Proteins
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SREBP cleavage-activating protein
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Sterol Regulatory Element Binding Protein 1
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Sterols
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Transcription Factors
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Brefeldin A
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Proprotein Convertases
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Serine Endopeptidases
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membrane-bound transcription factor peptidase, site 1