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.
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Osborne TF, Espenshade PJ.; ''Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Wang X, Sato R, Brown MS, Hua X, Goldstein JL.; ''SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Datta S, Osborne TF.; ''Activation domains from both monomers contribute to transcriptional stimulation by sterol regulatory element-binding protein dimers.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Brown MS, Goldstein JL.; ''Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL.''; PubMedEurope PMCScholia
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).
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.
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).
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.
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.
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.
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.
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).
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.
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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DataNodes
SCAP
Cop II CoatSCAP INSIG
oxysterolSCAP cholesterol
INSIGGTP Sec23p
Sec24pAnnotated Interactions
GTP Sec23p
Sec24p