Alternative titles; symbols
HGNC Approved Gene Symbol: SREBF2
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:41,833,105-41,907,305 (from NCBI)
The sterol regulatory element (SRE)-binding protein-2 (SREBP2) is structurally related to SREBP1 (SREBF1; 184756), and both control cholesterol homeostasis by stimulating transcription of sterol-regulated genes (summary by Osborne, 2001).
Hua et al. (1993) cloned SREBF2 from a HeLa cell cDNA library. The deduced 1,141-amino acid protein has a calculated molecular mass of 124 kD. SREBF2 has an acidic N-terminal domain, a basic helix-loop-helix leucine zipper (bHLH-ZIP) motif, and a long C terminus. It also has histidine, glutamic acid, and arginine residues implicated in DNA recognition by other bHLH-ZIP proteins. SREBF2 and SREBF1 share 47% amino acid identity overall and 71% identity in the bHLH-ZIP region. Northern blot analysis revealed a major SREBF2 transcript of 5.2 kb in all tissues examined. A minor transcript of about 4.2 kb was also observed.
Miserez et al. (1997) found that SREBP2 was expressed ubiquitously as 2 mRNAs (4.2 and 5.2 kb) that differ in their 3-prime untranslated regions because of different polyadenylation signals.
Miserez et al. (1997) found that the SREBF2 gene contains 19 exons and spans 72 kb, with a sterol regulatory element in the promoter region.
Hua et al. (1995) isolated a genomic cosmid clone for SREBF2 and mapped the gene to 22q13 by analysis of human/rodent somatic cell hybrids and fluorescence in situ hybridization.
By transfection of human 293 cells, Hua et al. (1993) found that SREBF2, like SREBF1, drove transcription from a reporter gene containing SRE1 in both the presence or absence of sterols.
Cholesterol homeostasis in animal cells is achieved by regulated cleavage of SREBPs, membrane-bound transcription factors. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein called SCAP (601510), which forms a complex with SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that SCAP escorts SREBPs from the endoplasmic reticulum (ER) to the Golgi, where SREBPs are cleaved by site-1 protease (S1P; 603355). The authors showed that sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviated the SCAP requirement and rendered cleavage insensitive to sterols. DeBose-Boyd et al. (1999) concluded that transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.
Shimano et al. (1997) concluded that SREBP2 can replace SREBP1 in regulating cholesterol synthesis in livers of mice and that the higher potency of SREBP2 leads to excessive hepatic cholesterol synthesis in these animals.
See review by Osborne (2001).
Najafi-Shoushtari et al. (2010) and Rayner et al. (2010) found that the microRNA miR33 (612156) embedded within intron 16 of the SREBP2 gene plays a role in control of cholesterol homeostasis through posttranscriptional repression of the adenosine triphosphate-binding cassette transporter A1 (ABCA1; 600046).
Jeon et al. (2008) found that the nuclear level of hepatic Srebp2 was elevated in mice fed a diet supplemented with lovastatin and ezetimibe (L/E) to limit dietary sterol absorption and reduce HMG-CoA reductase (HMGCR; 142910) activity. Genomic promoter-wide ChIP-chip analysis revealed that Srebp2 bound a number of promoters for genes encoding bitter taste-responding type-2 taste receptors (T2Rs; see 604867), which are expressed in gut enteroendocrine cells and in the tongue and oral cavity. Sterol depletion in the mouse enteroendocrine cell line STC-1, or expression of human SREBP2 in STC-1 cells, led to increased T2R expression. T2R expression was also increased in the proximal small intestine of L/E-treated mice. In contrast, T2R expression in the tongue was not induced by L/E feeding. Jeon et al. (2008) proposed that a low cholesterol diet may induce SREBP2-mediated activation of bitter signaling in the gut to prevent absorption of potentially toxic bitter substances in plant-derived foods, in addition to maximizing lipid uptake.
Crystal Structure
Lee et al. (2003) showed the crystal structure of importin-beta (see 602738) complexed with the active form of SREBP2. Importin-beta uses characteristic long helices like a pair of chopsticks to interact with an SREBP2 dimer. Importin-beta changes its conformation to reveal a pseudo-2-fold symmetry on its surface structure so that it can accommodate a symmetric dimer molecule.
Najafi-Shoushtari et al. (2010) identified the MIR33A gene within intron 16 of the SREBP2 gene. Brown et al. (2010) noted that the precursor for mature miR33A is found within the same intron of SREBP2 from many animal species, including large and small mammals, chickens, and frogs. There is even a perfectly conserved mature form of miR33A in the single SREBP-like gene of the fruit fly Drosophila melanogaster. The latter is most remarkable because insects do not synthesize sterols; their single SREBP gene controls fatty acid production. Moreover, the fruit fly genome does not contain ABCA1. While miR33A exhibits uniform conservation, miR33B (613486), present in intron 17 of the SREBP1 gene (184756), is present only in large mammals.
Yang et al. (1994) found a mutation in SREBF2 in a mutant CHO cell line that is resistant to transcriptional repression by 25-hydroxycholesterol. The truncated gene product activates the LDL receptor (606945) and HMG-CoA synthase (142940) genes independent of sterols. The authors speculated that mutations or polymorphisms in SREBF1 or SREBF2 could explain in part the wide variation in levels of LDL-cholesterol seen in the general population.
Muller and Miserez (2002) presented evidence suggesting that mutations in the SREBF2 gene are associated with hypercholesterolemia in man.
In Abcg5 (605459)/Abcg8 (605460)-deficient mice, Yang et al. (2004) demonstrated that accumulation of plant sterols perturbed cholesterol homeostasis in the adrenal gland, with a 91% reduction in its cholesterol content. Despite very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. In cultured adrenal cells, stigmasterol but not sitosterol inhibited SREBF2 processing and reduced cholesterol synthesis; stigmasterol also activated the liver X receptor (see LXRA; 602423) in a cell-based reporter assay. Yang et al. (2004) concluded that selected dietary plant sterols disrupt cholesterol homeostasis by affecting 2 critical regulatory pathways of lipid metabolism.
Lens opacity-13 (lop13) is a spontaneous autosomal recessive mouse mutant that exhibits nuclear cataracts. Merath et al. (2011) found that mature cataracts developed in lop13 mice by 10 weeks of age and that hypermature cataracts developed by 3 months of age. Histologic analysis of lop13 eyes revealed swollen lens fiber cells and the presence of bladder cells within the lens cortex, as well as morgagnian globules and liquefied material at the lens posterior. Lens epithelial cells at the anterior of the lens were normal. Lop13 mice also developed persistent skin wounds at around 3 months of age, although lop13 skin was indistinguishable from wildtype. Sequence analysis revealed a 3112C-T mutation in exon 18 of the Srebf2 gene in lop13 mice, resulting in the substitution of a highly conserved arginine within the Srebf2 regulatory domain with cysteine (R1038C). Biochemical analysis revealed significantly decreased cholesterol levels in lop13 brain and liver compared with wildtype; however, serum cholesterol levels were normal. Knockout of Srebf2 resulted in early embryonic lethality, but Srebf2 +/- mice appeared normal. Since the adult ocular lens is nonvascularized, Merath et al. (2011) hypothesized that SREBF2 and de novo cholesterol synthesis are essential for normal lens function.
Mukherjee et al. (2014) infected mouse macrophages with Leishmania donovani promastigotes and monitored their free cholesterol and esterified cholesterol levels. The authors showed that the initial interaction between macrophages and L. donovani enhanced free cholesterol, found predominantly in the plasma membrane, and caused a change in cell surface morphology with an upregulation of Hmgcr, which is regulated by Srebp2 after translocation of Srebp2 to the nucleus. Phagocytosis induced formation of lipid rafts containing activated Lyn (165120), which in turn activated the PI3K (see 601232)/AKT (see 164730) pathway and Srebp2. Silencing of Srebp2 with small interfering RNA reduced expression of Hmgcr, as well as plasma membrane cholesterol content and parasite survival. Inhibition of Srebp2 in infected mice drastically reduced spleen parasite burden. Mukherjee et al. (2014) proposed that induction of SREBP2 expression following L. donovani infection is associated with upregulation of plasma membrane cholesterol, suppression of reactive oxygen species generation, and induction of an antiinflammatory immune response to facilitate establishment of the infection.
Brown, M. S., Ye, J., Goldstein, J. L. HDL miR-ed down by SREBP introns. Science 328: 1495-1496, 2010. [PubMed: 20558698] [Full Text: https://doi.org/10.1126/science.1192409]
DeBose-Boyd, R. A., Brown, M. S., Li, W.-P., Nohturfft, A., Goldstein, J. L., Espenshade, P. J. Transport-dependent proteolysis of SREBP: relocation of Site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 99: 703-712, 1999. [PubMed: 10619424] [Full Text: https://doi.org/10.1016/s0092-8674(00)81668-2]
Hua, X., Wu, J., Goldstein, J. L., Brown, M. S., Hobbs, H. H. Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics 25: 667-673, 1995. [PubMed: 7759101] [Full Text: https://doi.org/10.1016/0888-7543(95)80009-b]
Hua, X., Yokoyama, C., Wu, J., Briggs, M. R., Brown, M. S., Goldstein, J. L., Wang, X. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc. Nat. Acad. Sci. 90: 11603-11607, 1993. [PubMed: 7903453] [Full Text: https://doi.org/10.1073/pnas.90.24.11603]
Jeon, T.-I., Zhu, B., Larson, J. L., Osborne, T. F. SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice. J. Clin. Invest. 118: 3693-3700, 2008. [PubMed: 18846256] [Full Text: https://doi.org/10.1172/JCI36461]
Lee, S. J., Sekimoto, T., Yamashita, E., Nagoshi, E., Nakagawa, A., Imamoto, N., Yoshimura, M., Sakai, H., Chong, K. T., Tsukihara, T., Yoneda, Y. The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor. Science 302: 1571-1575, 2003. [PubMed: 14645851] [Full Text: https://doi.org/10.1126/science.1088372]
Merath, K. M., Chang, B., Dubielzig, R., Jeannotte, R., Sidjanin, D. J. A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse. Mammalian Genome 22: 661-673, 2011. [PubMed: 21858719] [Full Text: https://doi.org/10.1007/s00335-011-9354-2]
Miserez, A. R., Cao, G., Probst, L. C., Hobbs, H. H. Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2). Genomics 40: 31-40, 1997. [PubMed: 9070916] [Full Text: https://doi.org/10.1006/geno.1996.4525]
Mukherjee, M., Basu Ball, W., Das, P. K. Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection. Int. J. Biochem. Cell Biol. 55: 196-208, 2014. [PubMed: 25218172] [Full Text: https://doi.org/10.1016/j.biocel.2014.08.019]
Muller, P. Y., Miserez, A. R. Identification of mutations in the gene encoding sterol regulatory element binding protein (SREBP)-2 in hypercholesterolaemic subjects. J. Med. Genet. 39: 271-275, 2002. [PubMed: 11950857] [Full Text: https://doi.org/10.1136/jmg.39.4.271]
Najafi-Shoushtari, S. H., Kristo, F., Li, Y., Shioda, T., Cohen, D. E., Gerszten, R. E., Naar, A. M. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328: 1566-1569, 2010. [PubMed: 20466882] [Full Text: https://doi.org/10.1126/science.1189123]
Osborne, T. F. CREating a SCAP-less liver keeps SREBPs pinned in the ER membrane and prevents increased lipid synthesis in response to low cholesterol and high insulin. Genes Dev. 15: 1873-1878, 2001. [PubMed: 11485982] [Full Text: https://doi.org/10.1101/gad.916601]
Rayner, K. J., Suarez, Y., Davalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., Fernandez-Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328: 1570-1573, 2010. [PubMed: 20466885] [Full Text: https://doi.org/10.1126/science.1189862]
Shimano, H., Shimomura, I., Hammer, R. E., Herz, J., Goldstein, J. L., Brown, M. S., Horton, J. D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Invest. 100: 2115-2124, 1997. [PubMed: 9329978] [Full Text: https://doi.org/10.1172/JCI119746]
Yang, C., Yu, L., Li, W., Xu, F., Cohen, J. C., Hobbs, H. H. Disruption of cholesterol homeostasis by plant sterols. J. Clin. Invest. 114: 813-822, 2004. [PubMed: 15372105] [Full Text: https://doi.org/10.1172/JCI22186]
Yang, J., Sato, R., Goldstein, J. L., Brown, M. S. Sterol-resistant transcription in CHO cells caused by gene rearrangement that truncates SREBP-2. Genes Dev. 8: 1910-1919, 1994. [PubMed: 7958866] [Full Text: https://doi.org/10.1101/gad.8.16.1910]