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

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1, 13, 19116, 8, 12, 171110-12, 15-17, 20202, 3, 5, 9, 12...Sar1bGTPSec23pSec24p SREBF1A,1C,2 SREBF1A,1C,2 SCAP tetramer SREBF1A,1C,2 cleaved by S2P SREBP1A/1C/2 Dimer SREBF1A,1C,2 SREBP1A/1C/2SCAP Sec23pSec24p Complex Sar1bGTPSec23pSec24p INSIG INSIG endoplasmic reticulum membraneSREBP1A/1C/2Importin beta-1 nucleoplasmSREBP1A/1C/2SCAP SREBP1A/1C/2Importin beta-1 SREBP1A/1C/2 Dimer SREBP1A/1C/2SCAPINSIGoxysterol INSIGoxysterol Sec24 Sec23pSec24p Complex SREBP1A/1C/2SCAPCop II Coat SCAP tetramer Golgi membraneSCAP tetramer SREBP1A/1C/2 Dimer INSIG SREBP1A/1C/2SCAPcholesterolINSIG SCAP tetramer Sar1bGTP Complex Ran-GTP SREBF1A,1C,2 cleaved by S2P SREBF1A,1C,2 SREBP1A/1C/2SCAP INSIGoxysterol Sec24 Sar1bGTP Complex SCAP tetramer SCAP tetramer SREBP1A/1C/2 Dimer SREBF1A,1C,2 Importin-betaRan GTP complex Ran-GTP cytosolSREBF1A,1C,2 cleaved by S2P SREBF1A,1C,2 cleaved by S2P SCAPcholesterol SAR1B INSIG2 SCAP SREBF1-3 SREBF1A,1C,2 cleaved by S2PINSIG1 SREBF1-1SREBF2SREBP1A/1C/2Importin beta-1SREBF1-1SREBF1-1SCAP SREBF2SREBP1A/1C/2Importin beta-1SREBF1-3 SREBF1-1 Cholesterol SCAP tetramerSREBF1A,1C,2 cleaved by S1PINSIGoxysterolSREBF2MBTPS2SEC24C oxysterol SREBP1A/1C/2 DimerSEC24A SEC24B SREBF2GTP Ran-GTPSEC23A SREBF2oxysterol RAN SREBF1-1SREBF1-3 SCAP SEC24B SEC24A INSIG2 KPNB1 KPNB1 Sar1bGTPSec23pSec24pINSIGSEC24D SREBF1-1 SREBP1A/1C/2SCAPCop II CoatRAN SEC24D SAR1B INSIG1 SREBP1A/1C/2SCAPImportin-betaRan GTP complexINSIG1 Activation of Gene Expression by SREBP SREBF1-3 SREBF1-3 SREBF2GTP SREBF1-3 SEC23A SREBP1A/1C/2SCAPcholesterolINSIGSREBF2SREBF2SREBF1-3 SREBF1-1 CholesterolSREBF1-1 GTP SREBP1A/1C/2SCAPINSIGoxysterolINSIG2 SCAP SREBF1-3 SREBF1-1 KPNB1SEC24C MBTPS1SREBP1A/1C/2 DimerSREBP1A/1C/2SCAPGTP SREBF2KPNB1 SCAP SCAP SREBF1-3 7141, 4, 1815, 2116


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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1655829

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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
  20. Brown MS, Goldstein JL.; ''Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL.''; PubMed Europe PMC Scholia
  21. Eberlé D, Hegarty B, Bossard P, Ferré P, Foufelle F.; ''SREBP transcription factors: master regulators of lipid homeostasis.''; PubMed Europe PMC Scholia

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 SREBP PathwayREACT_147904 (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).
Cholesterol MetaboliteCHEBI:16113 (ChEBI)
CholesterolMetaboliteCHEBI:16113 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
INSIG oxysterolComplexREACT_148530 (Reactome)
INSIG1 ProteinO15503 (Uniprot-TrEMBL)
INSIG2 ProteinQ9Y5U4 (Uniprot-TrEMBL)
INSIGProteinREACT_148176 (Reactome)
Importin-beta Ran GTP complexComplexREACT_9883 (Reactome)
KPNB1 ProteinQ14974 (Uniprot-TrEMBL)
KPNB1ProteinQ14974 (Uniprot-TrEMBL)
MBTPS1ProteinQ14703 (Uniprot-TrEMBL)
MBTPS2ProteinO43462 (Uniprot-TrEMBL)
RAN ProteinP62826 (Uniprot-TrEMBL)
Ran-GTPComplexREACT_8980 (Reactome)
SAR1B ProteinQ9Y6B6 (Uniprot-TrEMBL)
SCAP ProteinQ12770 (Uniprot-TrEMBL)
SCAP tetramerComplexREACT_147962 (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)
SREBF1-1ProteinP36956-1 (Uniprot-TrEMBL)
SREBF1-3 ProteinP36956-3 (Uniprot-TrEMBL)
SREBF1A,1C,2 cleaved by S1PProteinREACT_148635 (Reactome)
SREBF1A,1C,2 cleaved by S2PProteinREACT_148464 (Reactome)
SREBF2ProteinQ12772 (Uniprot-TrEMBL)
SREBP1A/1C/2 Importin beta-1ComplexREACT_148461 (Reactome)
SREBP1A/1C/2 Importin beta-1ComplexREACT_148551 (Reactome)
SREBP1A/1C/2

SCAP

Cop II Coat		ComplexREACT_147983 (Reactome)
SREBP1A/1C/2

SCAP INSIG

oxysterol		ComplexREACT_148296 (Reactome)
SREBP1A/1C/2

SCAP cholesterol

INSIG		ComplexREACT_147991 (Reactome)
SREBP1A/1C/2 SCAPComplexREACT_148317 (Reactome)
SREBP1A/1C/2 SCAPComplexREACT_148494 (Reactome)
SREBP1A/1C/2 DimerComplexREACT_117119 (Reactome)
SREBP1A/1C/2 DimerComplexREACT_148157 (Reactome)
Sar1b

GTP Sec23p

Sec24p		ComplexREACT_13151 (Reactome)
oxysterol MetaboliteCHEBI:53030 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CholesterolREACT_147892 (Reactome)
INSIG oxysterolREACT_147695 (Reactome)
INSIGREACT_147892 (Reactome)
Importin-beta Ran GTP complexArrowREACT_147724 (Reactome)
KPNB1REACT_147765 (Reactome)
MBTPS1REACT_147792 (Reactome)
MBTPS2REACT_147876 (Reactome)
REACT_147695 (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.
REACT_147718 (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).
REACT_147724 (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).
REACT_147765 (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).
REACT_147779 (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.
REACT_147789 (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.
REACT_147792 (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.
REACT_147876 (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.
REACT_147887 (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).
REACT_147892 (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.
Ran-GTPREACT_147724 (Reactome)
SCAP tetramerArrowREACT_147792 (Reactome)
SREBF1A,1C,2 cleaved by S1PArrowREACT_147792 (Reactome)
SREBP1A/1C/2 Importin beta-1REACT_147724 (Reactome)
SREBP1A/1C/2 SCAPREACT_147695 (Reactome)
SREBP1A/1C/2 SCAPREACT_147779 (Reactome)
SREBP1A/1C/2 SCAPREACT_147892 (Reactome)
SREBP1A/1C/2 DimerArrowREACT_147724 (Reactome)
SREBP1A/1C/2 DimerREACT_147765 (Reactome)
Sar1b

GTP Sec23p

Sec24p		REACT_147779 (Reactome)
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