SREBF2

This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif. Alternate splicing results in multiple transcript variants.

Full Name

Sterol Regulatory Element Binding Transcription Factor 2

Function

Sterol regulatory element-binding protein 2
Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 2), which is embedded in the endoplasmic reticulum membrane (PubMed:32322062).
Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis (PubMed:32322062).
Processed sterol regulatory element-binding protein 2
Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis (PubMed:12177166, PubMed:32322062).
Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:7903453, PubMed:12177166).
Regulates transcription of genes related to cholesterol synthesis pathway (PubMed:12177166, PubMed:32322062).

Biological Process

Biological Process cellular response to laminar fluid shear stress1 PublicationNAS:BHF-UCL
Biological Process cellular response to low-density lipoprotein particle stimulusManual Assertion Based On ExperimentIEP:BHF-UCL
Biological Process cellular response to starvationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Biological Process cholesterol homeostasisIEA:Ensembl
Biological Process cholesterol metabolic processIEA:UniProtKB-KW
Biological Process lipid metabolic processManual Assertion Based On ExperimentTAS:ProtInc
Biological Process negative regulation of cholesterol effluxManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process positive regulation of cholesterol biosynthetic processIDA:UniProtKB
Biological Process positive regulation of cholesterol storageManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process positive regulation of miRNA transcriptionIEA:Ensembl
Biological Process positive regulation of protein targeting to mitochondrionManual Assertion Based On ExperimentHMP:ParkinsonsUK-UCL
Biological Process positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process regulation of autophagy of mitochondrionManual Assertion Based On ExperimentHMP:ParkinsonsUK-UCL
Biological Process regulation of Notch signaling pathwayISS:UniProtKB
Biological Process regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process SREBP signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB

Cellular Location

Sterol regulatory element-binding protein 2
Endoplasmic reticulum membrane
Golgi apparatus membrane
Cytoplasmic vesicle, COPII-coated vesicle membrane
At high sterol concentrations, the SCAP-SREBP is retained in the endoplasmic reticulum (PubMed:32322062).
Low sterol concentrations promote recruitment into COPII-coated vesicles and transport of the SCAP-SREBP to the Golgi, where it is processed (PubMed:32322062).
Processed sterol regulatory element-binding protein 2
Nucleus
Transported into the nucleus with the help of importin-beta. Dimerization of the bHLH domain is a prerequisite for importin beta-dependent nuclear import.

Topology

Cytoplasmic: 1-479
Helical: 480-500
Lumenal: 501-533
Helical: 534-554
Cytoplasmic: 555-1139

PTM

Sterol regulatory element-binding protein 2
Processed in the Golgi apparatus, releasing the protein from the membrane (PubMed:8626610, PubMed:32322062, PubMed:9651382, PubMed:10805775).
At low cholesterol the SCAP-SREBP complex is recruited into COPII vesicles for export from the endoplasmic reticulum (PubMed:8626610, PubMed:32322062, PubMed:9651382, PubMed:10805775).
In the Golgi, complex SREBPs are cleaved sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) protease (PubMed:8626610, PubMed:9651382, PubMed:10805775, PubMed:32322062).
The first cleavage by site-1 protease occurs within the luminal loop, the second cleavage by site-2 protease occurs within the first transmembrane domain, releasing the transcription factor from the Golgi membrane (PubMed:9651382, PubMed:10805775).
Apoptosis triggers cleavage by the cysteine proteases caspase-3 and caspase-7. Cleavage and activation is induced by mediated cholesterol efflux (PubMed:8643593).
Phosphorylated by AMPK, leading to suppress protein processing and nuclear translocation, and repress target gene expression.
Processed sterol regulatory element-binding protein 2
Ubiquitinated; the nuclear form has a rapid turnover and is rapidly ubiquitinated and degraded by the proteasome in the nucleus.