Sterol-Regulated Release of SREBP-2 from Cell Membranes Requires Two Sequential Cleavages, One Within a Transmembrane Segment

Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH 2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras–SREBP-2 fusi...

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Bibliographic Details
Published in:Cell 1996-06, Vol.85 (7), p.1037-1046
Main Authors: Sakai, Juro, Duncan, Elizabeth A, Rawson, Robert B, Hua, Xianxin, Brown, Michael S, Goldstein, Joseph L
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Cell Line - cytology
Cell Line - drug effects
Cell Line - physiology
CHO Cells - cytology
CHO Cells - drug effects
CHO Cells - physiology
Cholesterol - biosynthesis
Cholesterol - genetics
Cricetinae
DNA, Complementary - genetics
DNA-Binding Proteins - drug effects
DNA-Binding Proteins - metabolism
Endopeptidases - metabolism
Epitopes - genetics
Humans
Immunoblotting
Kidney - cytology
Leucine Zippers - drug effects
Membrane Proteins - chemistry
Membrane Proteins - drug effects
Membrane Proteins - metabolism
Molecular Sequence Data
Mutagenesis, Site-Directed - genetics
ras Proteins - genetics
Recombinant Fusion Proteins - physiology
Sodium Bicarbonate
Sterol Regulatory Element Binding Protein 2
Sterols - pharmacology
Transcription Factors - drug effects
Transcription Factors - metabolism
Transcription, Genetic - genetics
Transfection
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Summary:Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH 2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras–SREBP-2 fusion proteins, we show that the NH 2-segment is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH 2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. Certain mutant Chinese hamster ovary cells are auxotrophic for cholesterol because they fail to carry out the second cleavage; the NH 2-segment remains membrane-bound and transcription is not activated.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)81304-5