Regulated Cleavage of Sterol Regulatory Element Binding Proteins Requires Sequences on Both Sides of the Endoplasmic Reticulum Membrane

AbstractSterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate a wide variety of genes involved in cholesterol and fatty acid synthesis. After transcription, SREBPs are controlled at multiple post-transcriptional levels, including proteolytic processing and post-translational modification. Among these, proteolytic processing is a crucial regulatory step that activates SREBPs, which are synthesized as inactive endoplasmic reticulum membrane proteins. In this review, we focus on recent progress with regard to signaling pathways and small molecules that affect activation of SREBPs by proteolytic processing.

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A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2

Biochemical Journal ◽

10.1042/0264-6021:3580415 ◽

2001 ◽

Vol 358 (2) ◽

pp. 415 ◽

Cited By ~ 5

Author(s):

Christopher R. IDDON ◽

Jane WILKINSON ◽

Andrew J. BENNETT ◽

Julie BENNETT ◽

Andrew M. SALTER ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cholesterol Ester ◽

Smooth Endoplasmic Reticulum ◽

Binding Protein ◽

Regulatory Element ◽

Membrane Cholesterol ◽

Endoplasmic Reticulum Membrane ◽

Intracellular Location ◽

Element Binding Protein ◽

Sterol Regulatory Element

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.162488899 ◽

2002 ◽

Vol 99 (20) ◽

pp. 12753-12758 ◽

Cited By ~ 345

Author(s):

D. Yabe ◽

M. S. Brown ◽

J. L. Goldstein

Keyword(s):

Endoplasmic Reticulum ◽

Binding Proteins ◽

Regulatory Element ◽

Endoplasmic Reticulum Protein ◽

Sterol Regulatory Element

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A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2

Biochemical Journal ◽

10.1042/bj3580415 ◽

2001 ◽

Vol 358 (2) ◽

pp. 415-422 ◽

Cited By ~ 7

Author(s):

Christopher R. IDDON ◽

Jane WILKINSON ◽

Andrew J. BENNETT ◽

Julie BENNETT ◽

Andrew M. SALTER ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cholesterol Ester ◽

Smooth Endoplasmic Reticulum ◽

Regulatory Element ◽

Membrane Cholesterol ◽

Endoplasmic Reticulum Membrane ◽

Cellular Cholesterol ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Coa Reductase

Cellular cholesterol homoeostasis is regulated through proteolysis of the membrane-bound precursor sterol-regulatory-element-binding protein (SREBP) that releases the mature transcription factor form, which regulates gene expression. Our aim was to identify the nature and intracellular site of the putative sterol-regulatory pool which regulates SREBP proteolysis in hamster liver. Cholesterol metabolism was modulated by feeding hamsters control chow, or a cholesterol-enriched diet, or by treatment with simvastatin or with the oral acyl-CoA:cholesterol acyltransferase inhibitor C1-1011 plus cholesterol. The effects of the different treatments on SREBP activation were confirmed by determination of the mRNAs for the low-density lipoprotein receptor and hydroxymethylglutaryl-CoA (HMG-CoA) reductase and by measurement of HMG-CoA reductase activity. The endoplasmic reticulum was isolated from livers and separated into subfractions by centrifugation in self-generating iodixanol gradients. Immunodetectable SREBP-2 accumulated in the smooth endoplasmic reticulum of cholesterol-fed animals. Cholesterol ester levels of the smooth endoplasmic reticulum membrane (but not the cholesterol levels) increased after cholesterol feeding and fell after treatment with simvastatin or C1-1011. The results suggest that an increased cellular cholesterol load causes accumulation of SREBP-2 in the smooth endoplasmic reticulum and, therefore, that membrane cholesterol ester may be one signal allowing exit of the SREBP-2/SREBP-cleavage-regulating protein complex to the Golgi.

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