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The SREBP pathway — insights from insigs and insects

Key Points

  • The SREBPs (sterol regulatory element binding proteins) are membrane-bound transcription factors that control lipid synthesis in animal cells. The transcriptionally active amino terminus is released from the membrane following two sequential proteolytic steps that are carried out by S1P and S2P.

  • Lipids control the release of active SREBP by regulating the access of the precursor protein, which is located in the endoplasmic reticulum (ER), to the proteases, S1P and S2P, which are found in the Golgi apparatus.

  • Movement of SREBP from the ER to the Golgi requires an escort factor, known as SCAP (SREBP-cleavage-activating protein). The amino-terminal half of SCAP consists of eight membrane-spanning helices, of which helices 2–6 comprise the sterol-sensing domain. SREBP and SCAP form a complex that is stable in both the presence and the absence of sterols. The SCAP's sterol-sensing domain is essential for transducing signals from cellular lipid concentrations to transport SREBP from the ER to the Golgi.

  • Two recently identified proteins, Insig-1 and Insig-2, are required for the sterol-mediated regulation of SCAP–SREBP movement. Point mutations within the SCAP sterol-sensing domain abolish sterol-mediated regulation and block the interaction between SCAP and Insig-1 or Insig-2. Insig-1 also interacts with the sterol-sensing domain of HMG CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, to regulate its stability.

  • Insects have all the known components of the SREBP pathway, except for the Insig proteins. Processing of SREBP in insects is regulated by phosphatidylethanolamine, rather than by sterols.

  • The suppressive action of two such different lipids on SREBP processing indicates that SCAP might sense physical properties of the membrane rather than interact with lipids in a classic receptor–ligand fashion.

Abstract

Animal cells coordinate lipid homeostasis by end-product feedback regulation of transcription. The control occurs through the proteolytic release of transcriptionally active sterol regulatory element binding proteins (SREBPs) from intracellular membranes. This feedback system has unexpected features that are found in all cells. Here, we consider recently discovered components of the regulatory machinery that govern SREBP processing, as well as studies in Drosophila that indicate an ancient role for the SREBP pathway in integrating membrane composition and lipid biosynthesis.

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Figure 1: Two-step processing of SREBP.
Figure 2: Components of the SREBP pathway in mammals and insects.
Figure 3: Sterol-regulated interaction between Insig and SCAP.
Figure 4: Dual roles of palmitate in the suppression of dSREBP cleavage.

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Acknowledgements

I am grateful to R. A. DeBose-Boyd, J. D. Horton and members of the Rawson laboratory for comments on this manuscript. This work is supported by grants from the American Heart Association, the National Institutes of Health and the Perot Family Foundation.

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DATABASES

LocusLink

Insig-1

Insig-2

NPC1

SREBPs

Swiss-Prot

HMG CoA reductase

S1P

S2P

SCAP

FURTHER INFORMATION

Genome Sequence of Ciona

Robert B. Rawson's laboratory

Glossary

SREBP

(Sterol regulatory element binding protein). A transcription factor in animal cells that is necessary for the transcriptional activation of genes required for lipid synthesis.

RIP

(Regulated intramembrane proteolysis). The cleavage of a protein within a membrane-spanning helix to release a functional domain. This cleavage usually follows an initial, regulated cleavage that occurs in the extracytoplasmic domain of the substrate.

S1P

(Site-1 protease). A membrane-anchored subtilisin-like serine protease of the secretory pathway, the active site of which is in the lumen.

S2P

(Site-2 protease). An unusually hydrophobic metalloproteinase that cleaves its substrates within membrane-spanning helices.

SCAP

(SREBP-cleavage-activating protein). A large, polytopic membrane protein that senses cellular sterol concentrations and escorts SREBP from the ER to the Golgi apparatus.

COPII

Coatamer protein complex II, which is required for intracellular vesicle formation.

INSIG

A membrane protein of the endoplasmic reticulum (ER) that interacts with the sterol-sensing domain of SCAP and serves to retain the SCAP–SREBP complexes within the ER.

HMG CoA

(3-hydroxy-3-methylglutaryl coenzyme A). The activated species that is reduced to form mevalonate, the precursor of cholesterol and isoprenoid compounds.

STEROL-SENSING DOMAIN

A motif of five transmembrane helices that is found in SCAP and HMG CoA reductase where it mediates protein movement or stability through interaction with the Insig proteins. Similar domains are present in other proteins associated with cholesterol metabolism, such as the Niemann–Pick C disease protein and the Hedgehog receptor, Patched.

UNFOLDED PROTEIN RESPONSE

An intracellular signalling pathway that connects the endoplasmic reticulum (ER) with the nucleus. Under stress conditions (when unfolded proteins accumulate in the ER), cells react by the increased transcription of chaperone genes. These chaperones are required for the maintenance of protein folding.

ER STRESS

A cellular response to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). Although a normal physiological phenomenon, it can also be provoked by several conditions, such as viral infections and mutations that impair protein folding.

MEVALONATE PATHWAY

The series of enzymes, and the reactions they catalyse, that convert acetyl coenzyme A to many different hydrophobic products such as farnesol, geranylgeranol, dolichol, and, in vertebrate animals, cholesterol.

RNAi

RNA-mediated interference of gene expression. The process whereby the introduction of double-stranded RNA into a cell elicits a response that catalytically destroys single-stranded RNAs that contain the cognate sequence.

PHOSPHATIDYLETHANOLAMINE

A phospholipid with the unusually small headgroup ethanolamine attached to its diacylglycerol backbone.

HII PHASE

Lipids that form tubular structures following hydration, wherein the hydrophilic moieties are facing the inner surface of a tube, and the hydrophobic moieties face outward. As a result, multiple tubes associate through hydrophobic interactions, yielding a structure that seems hexagonal in cross section.

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Rawson, R. The SREBP pathway — insights from insigs and insects. Nat Rev Mol Cell Biol 4, 631–640 (2003). https://doi.org/10.1038/nrm1174

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