Regulation of cholesterol biosynthesis by SREBP (SREBF) (Homo sapiens)

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3, 10, 132, 4, 16, 19-212, 7, 12, 16112, 6, 9, 11, 14...1118endoplasmic reticulum membranenucleoplasmGolgi membranecytosolSCAP SREBP1A,1C,2:Importin beta-1Ran-GTPKPNB1 SREBF1-3 SREBF2(1-484) SAR1B SEC23A INSIG2 SREBF1-3 SEC24B GTP SEC24D SREBF1-1(1-490) RAN SREBF2(1-1141) CHOL SREBF1-1 KPNB1 SREBF1A,1C,2 cleavedby S1PINSIG1 SREBF1-3 SEC23A SREBP1A,1C,2:SCAPSREBF1-3 GTP INSIG1 SREBF2(1-1141) SCAP tetramerINSIG2 SEC24A INSIG:oxysterolSREBF1-3 SREBF2(1-1141) SREBF1-1(1-490) Importin-beta:RanGTP complexSREBF1-3 INSIG1 SEC24C SREBF1A,1C,2 cleavedby S2PActivation of geneexpression by SREBF(SREBP)SREBF1-1(1-490) SCAP GTP SREBF1-1 SREBF2(1-1141) oxysterol oxysterol KPNB1 GTP SREBP1A,1C,2:SCAP:Cop II CoatSREBF1-1 SREBF1-1 SREBF2(1-484) SREBP1A,1C,2:SCAP:cholesterol:INSIGMBTPS2SCAP SREBP1A,1C,2:Importin beta-1SREBF1-3 MBTPS1SREBP1A,1C,2 dimerSCAP INSIGSREBP1A,1C,2:SCAP:INSIG:oxysterolSREBF2(1-484) SCAP RAN Sar1b:GTP:Sec23p:Sec24pSREBF1-1 SEC24C INSIG2 SREBF1-3 SAR1B SREBP1A,1C,2:SCAPSREBF2(1-484) KPNB1SEC24D SREBF2(1-1141) SEC24A SREBF1-1(1-490) SCAP SREBF1-3 CHOLSEC24B SREBP1A,1C,2 dimer14, 1751, 3, 8159


Description

Sterol regulatory element binding proteins (SREBPs, SREBFs) respond to low cholesterol concentrations by transiting to the nucleus and activating genes involved in cholesterol and lipid biosynthesis (reviewed in Brown and Goldstein 2009, Osborne and Espenshade 2009, Weber et al. 2004).
Newly synthesized SREBPs are transmembrane proteins that bind SCAP in the endoplasmic reticulum (ER) membrane. SCAP binds cholesterol which causes a conformational change that allows SCAP to interact with INSIG, retaining the SCAP:SREBP complex in the ER. INSIG binds oxysterols, which cause INSIG to bind SCAP and retain SCAP:SREBP in the endoplasmic reticulum.
In low cholesterol (below about 5 mol%) SCAP no longer interacts with cholesterol or INSIG and binds Sec24 of the CopII coat complex instead. Thus SCAP:SREBP transits with the CopII complex from the ER to the Golgi. In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. The N-terminal fragment is imported to the nucleus by importin-beta and then acts with other factors, such as SP1 and NF-Y, to activate transcription of target genes. Targets of SREBP include the genes encoding all enzymes of cholesterol biosynthesis and several genes involved in lipogenesis. SREBP2 most strongly activates cholesterol biosynthesis while SREBP1C most strongly activates lipogenesis. Source:Reactome.

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Bibliography

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  1. Sakai J, Nohturfft A, Goldstein JL, Brown MS.; ''Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies.''; PubMed Europe PMC Scholia
  2. Zoumi A, Datta S, Liaw LH, Wu CJ, Manthripragada G, Osborne TF, Lamorte VJ.; ''Spatial distribution and function of sterol regulatory element-binding protein 1a and 2 homo- and heterodimers by in vivo two-photon imaging and spectroscopy fluorescence resonance energy transfer.''; PubMed Europe PMC Scholia
  3. Párraga A, Bellsolell L, Ferré-D'Amaré AR, Burley SK.; ''Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution.''; PubMed Europe PMC Scholia
  4. Osborne TF, Espenshade PJ.; ''Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been.''; PubMed Europe PMC Scholia
  5. Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL.; ''Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment.''; PubMed Europe PMC Scholia
  6. Wang X, Sato R, Brown MS, Hua X, Goldstein JL.; ''SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis.''; PubMed Europe PMC Scholia
  7. Weber LW, Boll M, Stampfl A.; ''Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins.''; PubMed Europe PMC Scholia
  8. Touré BB, Munzer JS, Basak A, Benjannet S, Rochemont J, Lazure C, Chrétien M, Seidah NG.; ''Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment.''; PubMed Europe PMC Scholia
  9. Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL.; ''Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig.''; PubMed Europe PMC Scholia
  10. Lee SJ, Sekimoto T, Yamashita E, Nagoshi E, Nakagawa A, Imamoto N, Yoshimura M, Sakai H, Chong KT, Tsukihara T, Yoneda Y.; ''The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor.''; PubMed Europe PMC Scholia
  11. Shin ES, Lee HH, Cho SY, Park HW, Lee SJ, Lee TR.; ''Genistein downregulates SREBP-1 regulated gene expression by inhibiting site-1 protease expression in HepG2 cells.''; PubMed Europe PMC Scholia
  12. Yabe D, Brown MS, Goldstein JL.; ''Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins.''; PubMed Europe PMC Scholia
  13. Espenshade PJ, Cheng D, Goldstein JL, Brown MS.; ''Autocatalytic processing of site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins.''; PubMed Europe PMC Scholia
  14. Nagoshi E, Yoneda Y.; ''Dimerization of sterol regulatory element-binding protein 2 via the helix-loop-helix-leucine zipper domain is a prerequisite for its nuclear localization mediated by importin beta.''; PubMed Europe PMC Scholia
  15. Rawson RB, Zelenski NG, Nijhawan D, Ye J, Sakai J, Hasan MT, Chang TY, Brown MS, Goldstein JL.; ''Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.''; PubMed Europe PMC Scholia
  16. Pai JT, Guryev O, Brown MS, Goldstein JL.; ''Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins.''; PubMed Europe PMC Scholia
  17. Datta S, Osborne TF.; ''Activation domains from both monomers contribute to transcriptional stimulation by sterol regulatory element-binding protein dimers.''; PubMed Europe PMC Scholia
  18. Nagoshi E, Imamoto N, Sato R, Yoneda Y.; ''Nuclear import of sterol regulatory element-binding protein-2, a basic helix-loop-helix-leucine zipper (bHLH-Zip)-containing transcription factor, occurs through the direct interaction of importin beta with HLH-Zip.''; PubMed Europe PMC Scholia
  19. Ye J, Davé UP, Grishin NV, Goldstein JL, Brown MS.; ''Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease.''; PubMed Europe PMC Scholia
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History

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CompareRevisionActionTimeUserComment
114831view16:33, 25 January 2021ReactomeTeamReactome version 75
113277view11:34, 2 November 2020ReactomeTeamReactome version 74
112489view15:44, 9 October 2020ReactomeTeamReactome version 73
101401view11:28, 1 November 2018ReactomeTeamreactome version 66
100939view21:04, 31 October 2018ReactomeTeamreactome version 65
100476view19:38, 31 October 2018ReactomeTeamreactome version 64
100021view16:22, 31 October 2018ReactomeTeamreactome version 63
99574view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99196view12:43, 31 October 2018ReactomeTeamreactome version 62
93752view13:33, 16 August 2017ReactomeTeamreactome version 61
93272view11:18, 9 August 2017ReactomeTeamreactome version 61
88136view12:53, 26 July 2016RyanmillerOntology Term : 'lipid metabolic pathway' added !
88135view12:52, 26 July 2016RyanmillerOntology Term : 'lipoprotein metabolic pathway' added !
88134view12:52, 26 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86349view09:15, 11 July 2016ReactomeTeamreactome version 56
83194view10:19, 18 November 2015ReactomeTeamVersion54
81751view09:51, 26 August 2015ReactomeTeamVersion53
76888view08:16, 17 July 2014ReactomeTeamFixed remaining interactions
76593view11:57, 16 July 2014ReactomeTeamFixed remaining interactions
75924view09:58, 11 June 2014ReactomeTeamRe-fixing comment source
75626view10:49, 10 June 2014ReactomeTeamReactome 48 Update
74981view13:50, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74625view08:40, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
Activation of gene

expression by SREBF

(SREBP)		PathwayR-HSA-2426168 (Reactome) After transiting to the nucleus SREBPs (SREBP1A/1C/2, SREBFs) bind short sequences, sterol regulatory elements (SREs), in the promoters of target genes (reviewed in Eberle et al. 2004, Weber et al. 2004). SREBPs alone are relatively weak activators of transcription, with SREBP1C being significantly weaker than SREBP1A or SREBP2. In combination with other transcription factors such as SP1 and NF-Y the SREBPs are much stronger activators. SREBP1C seems to more specifically target genes involved in fatty acid synthesis while SREBP2 seems to target genes involved in cholesterol synthesis (Pai et al. 1998).
CHOL MetaboliteCHEBI:16113 (ChEBI)
CHOLMetaboliteCHEBI:16113 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
INSIG1 ProteinO15503 (Uniprot-TrEMBL)
INSIG2 ProteinQ9Y5U4 (Uniprot-TrEMBL)
INSIG:oxysterolComplexR-HSA-2317517 (Reactome)
INSIGR-HSA-1655749 (Reactome)
Importin-beta:Ran GTP complexComplexR-HSA-180719 (Reactome)
KPNB1 ProteinQ14974 (Uniprot-TrEMBL)
KPNB1ProteinQ14974 (Uniprot-TrEMBL)
MBTPS1ProteinQ14703 (Uniprot-TrEMBL)
MBTPS2ProteinO43462 (Uniprot-TrEMBL)
RAN ProteinP62826 (Uniprot-TrEMBL)
Ran-GTPComplexR-HSA-180738 (Reactome)
SAR1B ProteinQ9Y6B6 (Uniprot-TrEMBL)
SCAP ProteinQ12770 (Uniprot-TrEMBL)
SCAP tetramerComplexR-HSA-1655737 (Reactome)
SEC23A ProteinQ15436 (Uniprot-TrEMBL)
SEC24A ProteinO95486 (Uniprot-TrEMBL)
SEC24B ProteinO95487 (Uniprot-TrEMBL)
SEC24C ProteinP53992 (Uniprot-TrEMBL)
SEC24D ProteinO94855 (Uniprot-TrEMBL)
SREBF1-1 ProteinP36956-1 (Uniprot-TrEMBL)
SREBF1-1(1-490) ProteinP36956-1 (Uniprot-TrEMBL)
SREBF1-3 ProteinP36956-3 (Uniprot-TrEMBL)
SREBF1A,1C,2 cleaved by S1PR-HSA-1655726 (Reactome)
SREBF1A,1C,2 cleaved by S2PR-HSA-1655732 (Reactome)
SREBF2(1-1141) ProteinQ12772 (Uniprot-TrEMBL)
SREBF2(1-484) ProteinQ12772 (Uniprot-TrEMBL)
SREBP1A,1C,2 dimerComplexR-HSA-1655744 (Reactome)
SREBP1A,1C,2 dimerComplexR-HSA-2065548 (Reactome)
SREBP1A,1C,2:Importin beta-1ComplexR-HSA-2065543 (Reactome)
SREBP1A,1C,2:Importin beta-1ComplexR-HSA-2065556 (Reactome)
SREBP1A,1C,2:SCAP:Cop II CoatComplexR-HSA-1655765 (Reactome)
SREBP1A,1C,2:SCAP:INSIG:oxysterolComplexR-HSA-2317522 (Reactome)
SREBP1A,1C,2:SCAP:cholesterol:INSIGComplexR-HSA-1655766 (Reactome)
SREBP1A,1C,2:SCAPComplexR-HSA-1655742 (Reactome)
SREBP1A,1C,2:SCAPComplexR-HSA-2317520 (Reactome)
Sar1b:GTP:Sec23p:Sec24pComplexR-HSA-203997 (Reactome)
oxysterol MetaboliteCHEBI:53030 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CHOLR-HSA-2317530 (Reactome)
INSIG:oxysterolR-HSA-2317531 (Reactome)
INSIGR-HSA-2317530 (Reactome)
Importin-beta:Ran GTP complexArrowR-HSA-2065539 (Reactome)
KPNB1R-HSA-2065550 (Reactome)
MBTPS1mim-catalysisR-HSA-1655842 (Reactome)
MBTPS2mim-catalysisR-HSA-1655851 (Reactome)
R-HSA-1655825 (Reactome) SREBPs (SREBP1A, SREBP1C, SREBP2, also known as SREBFs) are transmembrane proteins that bind SCAP in the endoplasmic reticulum membrane. In the presence of cholesterol or oxysterols SCAP:SREBP1A/1C/2 binds INSIG and is retained in the endoplasmic reticulum. At cholesterol concentrations below 5 mol% SCAP changes conformation, SCAP:SREBP1A/1C/2 loses interaction with INSIG, binds the CopII coat complex, and is translocated to the Golgi.
R-HSA-1655831 (Reactome) The N-terminal domain of SREBP1A/1C/2 (SREBF1A/1C/2) dimerizes and is imported from the cytosol into the nucleus by importin-beta (Nagoshi et al. 1999, Nagoshi and Yoned 2001, Lee et al. 2003). In the nucleus the dimers bind DNA (Parraga et al. 1998) and activate transcription (Datta and Osborne 2005).
R-HSA-1655834 (Reactome) In low concentrations of cholesterol SCAP interacts with Sec24 of the CopII coat complex causing SCAP:SREBP1A/1C/2 to be transported with the CopII complex from the endoplasmic reticulum to the Golgi.
R-HSA-1655842 (Reactome) S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2, which remains bound to the membrane.
R-HSA-1655851 (Reactome) S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol.
R-HSA-2065539 (Reactome) SREBP1A/1C/2 (SREBF1A/1C/2) dimer dissociates from Importin beta-1 in response to Ran-GTP in the nucleoplasm (Nagoshi et al. 1999).
R-HSA-2065549 (Reactome) The N-terminal domains of SREBPs (SREBP1A/1C/2, SREBFs) dimerize via interaction of their helix-loop-helix leucine zipper domains (Nagoshi and Yoneda 2001).
R-HSA-2065550 (Reactome) SREBP1A/1C/2 (SREBF1A/1C/2) dimer binds Importin beta-1 via the helix-loop-helix leucine zipper domain of SREBP1A/1C/2 (Nagoshi et al. 1999).
R-HSA-2317530 (Reactome) SREBPs (SREBP1A/1C/2, SREBFs) bind SCAP in the endoplasmic reticulum membrane. Luminal loop 1 of SCAP binds cholesterol which prevents SCAP from interacting with Sec24 in the CopII coat complex and allows SCAP to interact with INSIG instead. These interactions retain SCAP:SREBP1A/1C/2 in the endoplasmic reticulum. The order of assembly of the SREBP1A/1C/2:SCAP:cholesterol:INSIG complex is unknown.
R-HSA-2317531 (Reactome) INSIG binds oxysterols and the INSIG:oxysterol complex interacts with SCAP subunits of the SREBP1A/1C/2:SCAP (SREBF1A/1C/2:SCAP) complex. This interaction retains the SREBP1A/1C/2:SCAP:INSIG:oxysterol complex in the endoplasmic reticulum. The order of assembly of the SREBP1A/1C/2:SCAP:INSIG:oxysterol complex is unknown.
Ran-GTPR-HSA-2065539 (Reactome)
SCAP tetramerArrowR-HSA-1655842 (Reactome)
SREBF1A,1C,2 cleaved by S1PArrowR-HSA-1655842 (Reactome)
SREBF1A,1C,2 cleaved by S1PR-HSA-1655851 (Reactome)
SREBF1A,1C,2 cleaved by S2PArrowR-HSA-1655851 (Reactome)
SREBF1A,1C,2 cleaved by S2PR-HSA-2065549 (Reactome)
SREBP1A,1C,2 dimerArrowR-HSA-2065539 (Reactome)
SREBP1A,1C,2 dimerArrowR-HSA-2065549 (Reactome)
SREBP1A,1C,2 dimerR-HSA-2065550 (Reactome)
SREBP1A,1C,2:Importin beta-1ArrowR-HSA-1655831 (Reactome)
SREBP1A,1C,2:Importin beta-1ArrowR-HSA-2065550 (Reactome)
SREBP1A,1C,2:Importin beta-1R-HSA-1655831 (Reactome)
SREBP1A,1C,2:Importin beta-1R-HSA-2065539 (Reactome)
SREBP1A,1C,2:SCAP:Cop II CoatArrowR-HSA-1655825 (Reactome)
SREBP1A,1C,2:SCAP:Cop II CoatR-HSA-1655834 (Reactome)
SREBP1A,1C,2:SCAP:INSIG:oxysterolArrowR-HSA-2317531 (Reactome)
SREBP1A,1C,2:SCAP:cholesterol:INSIGArrowR-HSA-2317530 (Reactome)
SREBP1A,1C,2:SCAPArrowR-HSA-1655834 (Reactome)
SREBP1A,1C,2:SCAPR-HSA-1655825 (Reactome)
SREBP1A,1C,2:SCAPR-HSA-1655842 (Reactome)
SREBP1A,1C,2:SCAPR-HSA-2317530 (Reactome)
SREBP1A,1C,2:SCAPR-HSA-2317531 (Reactome)
Sar1b:GTP:Sec23p:Sec24pR-HSA-1655825 (Reactome)
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