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The SREBP regulatory pathway.[1]
sterol regulatory element binding transcription factor 1
Identifiers
Symbol SREBF1
Entrez 6720
HUGO 11289
OMIM 184756
RefSeq NM_004176
UniProt P36956
Other data
Locus Chr. 17 p11.2
sterol regulatory element binding transcription factor 2
Identifiers
Symbol SREBF2
Entrez 6721
HUGO 11290
OMIM 600481
RefSeq NM_004599
UniProt Q12772
Other data
Locus Chr. 22 q13

Sterol Regulatory Element Binding Proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors.[2] Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis.[3][4] Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

Contents

Mechanism of action

Beginning with the discovery of the Sterol Regulatory Element Binding Proteins (SREBPs) in 1993,[2] a productive combination of biochemistry, molecular biology and genetics, has brought to light the complex mechanisms by which animal cells maintain the proper levels of intracellular lipid (fats and oils) in the face of widely varying circumstances (lipid homeostasis).[1][5][6] These studies exposed a signaling mechanism of beguiling complexity that is responsible for the end-product feedback regulation of gene transcription. For example, when cellular cholesterol levels fall below the level needed, the cell makes more of the enzymes necessary to make cholesterol. A principal step in this response is to make more of the mRNA transcripts that direct the synthesis of these enzymes. Conversely, when there is enough cholesterol around, the cell stops making those mRNAs and the level of the enzymes falls. As a result, the cell quits making cholesterol once it has enough.

A notable feature of this regulatory feedback machinery was first observed for the SREBP pathway - regulated intramembrane proteolysis (Rip). Subsequently, Rip was found to be used in almost all organisms from bacteria to human beings and regulates a wide range of processes ranging from development to neurodegeneration.

The defining feature of the SREBP pathway is the proteolytic release of a membrane-bound transcription factor, SREBP. Proteolytic cleavage frees it to move through the cytoplasm to the nucleus. Once in the nucleus, SREBP can bind to specific DNA sequences (the sterol regulatory elements or SREs) that are found in the control regions of the genes that encode enzymes needed to make lipids. This binding to DNA leads to the increased transcription of the target genes.

The ~120 kDa SREBP precursor protein is anchored in the membranes of the endoplasmic reticulum (ER) and nuclear envelope by virtue of two membrane-spanning helices in the middle of the protein. The precursor has a hairpin orientation in the membrane, so that both the amino-terminal transcription factor domain and the COOH-terminal regulatory domain face the cytoplasm. The two membrane-spanning helices are separated by a loop of about 30 amino acids that lies in the lumen of the ER. Two separate, site-specific proteolytic cleavages are necessary for release of the transcriptionally active amino-terminal domain. These cleavages are carried out by two distinct proteases, called site-1 protease (S1P) and site-2 protease (S2P).

In addition to S1P and S2P, the regulated release of transcriptionally active SREBP requires the cholesterol-sensing protein SREBP cleavage activating protein (Scap), which forms a complex with SREBP owing to interaction between their respective carboxy-terminal domains. Scap, in turn can bind reversibly with another ER-resident membrane protein, Insig. In the presence of sterols, which bind to Insig and Scap, Insig and Scap also bind one another. Insig always stays in the ER membrane and thus the SREBP:Scap complex remains in the ER when Scap is bound to Insig. When sterol levels are low, Insig and Scap no longer bind. Then, Scap undergoes a conformational change that exposes a portion of the protein ('MELADL') that signals it to be included as cargo in the COPII vesicles that move from the ER to the Golgi apparatus. In these vesicles, Scap, dragging SREBP along with it, is transported to the Golgi. The regulation of SREBP cleavage employs a notable feature of eukaryotic cells, subcellular compartmentalization defined by intracellular membranes, to ensure that cleavage occurs only when needed.

Once in the Golgi apparatus, the SREBP:Scap complex encounters active S1P. S1P cleaves SREBP at site-1, cutting it into two halves. Because each half still has a membrane-spanning helix, each remains bound in the membrane. The newly generated amino-terminal half of SREBP (which is the ‘business end' of the molecule) then goes on to be cleaved at site-2 that lies within its membrane-spanning helix. This is the work of S2P, an unusual metalloprotease. This releases the cytoplasmic portion of SREBP, which then travels to the nucleus where it activates transcription of target genes (e.g. LDL receptor gene)

Isoforms

Mammalian genomes have two separate SREBP genes (SREBF1 and SREBF2):

  • SREBP-1 expression produces two different isoforms, SREBP-1a and -1c. These isoforms differ in their first exons owing to the use of different transcriptional start sites for the SREBP-1 gene. SREBP-1c was also identified in rats as ADD-1. SREBP-1c is responsible for regulating the genes needed to make fatty acids.
  • SREBP-2. SREBP-2 regulates the genes of cholesterol metabolism.

References

  1. ^ a b Brown MS, Goldstein JL (1997). "The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor". Cell 89 (3): 331–40. doi:10.1016/S0092-8674(00)80213-5. PMID 9150132.  
  2. ^ a b Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS (1993). "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene". Cell 75 (1): 187–97. PMID 8402897. http://www.cell.com/content/article/abstract?uid=PII009286749390690R.  
  3. ^ Wang X, Sato R, Brown MS, Hua X, Goldstein JL (1994). "SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis". Cell 77 (1): 53–62. doi:10.1016/0092-8674(94)90234-8. PMID 8156598.  
  4. ^ Gasic GP (1994). "Basic-helix-loop-helix transcription factor and sterol sensor in a single membrane-bound molecule". Cell 77 (1): 17–9. doi:10.1016/0092-8674(94)90230-5. PMID 8156593.  
  5. ^ Brown MS, Goldstein JL (1999). "A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood". Proc. Natl. Acad. Sci. U.S.A. 96 (20): 11041–8. doi:10.1073/pnas.96.20.11041. PMID 10500120.  
  6. ^ Brown MS, Ye J, Rawson RB, Goldstein JL (2000). "Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans". Cell 100 (4): 391–8. doi:10.1016/S0092-8674(00)80675-3. PMID 10693756.  

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