The SREBP pathway - Insights from insigs and insects

Nature Reviews Molecular Cell Biology

Volumn 4, Issue 8, 2003, Pages 631-640

  Rawson, Robert B ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 DEHYDROCHOLESTEROL; ACETYL COENZYME A CARBOXYLASE; ACETYL COENZYME A SYNTHETASE; ACYL COENZYME A DESATURASE; ADENOSINE TRIPHOSPHATE CITRATE LYASE; CARBOXYLYASE; FARNESYL TRANS TRANSFERASE; FATTY ACID; FATTY ACID SYNTHASE; GERANYLTRANSFERASE; GLYCEROL 3 PHOSPHATE ACYLTRANSFERASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; HYDROXYMETHYLGLUTARYL COENZYME A SYNTHASE; INSIG1 PROTEIN; LANOSTEROL SYNTHASE; LATHOSTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; MEMBRANE PROTEIN; MEVALONIC ACID; PALMITIC ACID; PHOSPHATIDYLETHANOLAMINE; PHOSPHOLIPID; PROTEIN KINASE; PROTEINASE; SCAP PROTEIN; SQUALENE MONOOXYGENASE; SQUALENE SYNTHASE; STEROL; STEROL REGULATORY ELEMENT BINDING PROTEIN; TRANSCRIPTION FACTOR; UNCLASSIFIED DRUG;

BIOSYNTHESIS; DROSOPHILA; ENDOPLASMIC RETICULUM; FEEDBACK SYSTEM; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; INSECT; LIPID METABOLISM; LIPOGENESIS; MEMBRANE; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; REVIEW; TRANSCRIPTION REGULATION;

ANIMALS; CCAAT-ENHANCER-BINDING PROTEINS; CELL MEMBRANE; DNA-BINDING PROTEINS; HUMANS; INSECT PROTEINS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LIPID METABOLISM; LIPIDS; MEMBRANE PROTEINS; METALLOENDOPEPTIDASES; MOLECULAR STRUCTURE; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; STEROLS; TRANSCRIPTION FACTORS;

ANIMALIA; HEXAPODA; INSECTA;

EID: 0043172415     PISSN: 14710072     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrm1174     Document Type: Review

References (81)

1. Brown, M. S., Ye, J., Rawson, R. B. & Goldstein, J. L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans Cell 100, 391-398 (2000). Establishes the phenomenon of regulated intramembrane proteolysis as a widespread and ancient signal-transduction mechanism and describes several examples from animals and prokaryotes.
2. Brown, M. S. & Goldstein, J. L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl Acad. Sci. USA 96, 11041-11048 (1999).
3. Nohturfft, A., Yabe, D., Goldstein, J. L., Brown, M. S. & Espenshade, P. J. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102, 315-323 (2000).
4. Espenshade, P. J., Li, W. P. & Yabe, D. Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc. Natl Acad. Sci. USA 99, 11694-11699 (2002)
5. Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver J. Clin. Invest. 109, 1125-1131 (2002).
6. Tontonoz, P., Kim, J. B., Graves, R. A. & Spiegelman, B. M. ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol. Cell Biol. 13, 4753-4759 (1993).
7. Goldstein, J. L., Rawson, R. B. & Brown, M. S. Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch. Biochem. Biophys. 397, 139-148 (2002).
8. Wang, X. et al. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. J. Biol. Chem. 268, 14497-14504 (1993).
9. Briggs, M. R., Yokoyama, C., Wang, X., Brown, M. S. & Goldstein, J. L. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence J. Biol. Chem. 268, 14490-14496 (1993). References 8 and 9 describe the original identification of SREBP.
10. Sudhof, T. C., Russell, D. W., Brown, M. S. & Goldstein, J. L. 42 bp element from LDL receptor gene confers end-product repression by sterols when inserted into viral TK promoter. Cell 48, 1061-1069 (1987).
11. Dawson, P. A. et al. Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor Sp1. J. Biol. Chem. 263, 3372-3379 (1988).
12. Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331-340 (1997).
13. Yokoyama, C. et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75, 187-197 (1993).
14. Hua, X. et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element, Proc. Natl Acad. Sci. USA 90, 11603-11607 (1993).
15. Sato, R. et al. Assignment of the membrane attachment, DNA binding, and transcriptional activation domains of sterol regulatory element-binding protein-1 (SREBP-1) J. Biol. Chem. 269, 17267-17273 (1994).
16. Wang, X., Sato, R., Brown, M. S., Hua, X. & Goldstein, J. L. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77, 53-62 (1994). Describes the sterol-regulated proteolysis of SREBP.
17. 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).
18. Yang, J., Brown, M. S., Ho, Y. K. & Goldstein, J. L. Three different rearrangements in a single intron truncate sterol regulatory element binding protein-2 and produce sterol-resistant phenotype in three cell lines. Role of introns in protein evolution. J. Biol. Chem. 270, 12152-12161 (1995).
19. Shimano, H. et al. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1 a in livers of transgenic mice and in cultured cells. J. Clin. Invest. 99, 846-854 (1997).
20. Pai, J. T., Guryev, O., Brown, M. S. & Goldstein, J. L. Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins. J. Biol. Chem. 273, 26138-26148 (1998).
21. Horton, J. D. et al. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J. Clin. Invest. 101, 2331-2339 (1998).
22. Carstea, E. D. et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228-231 (1997).
23. Loftus, S. K. et al. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277, 232-235 (1997).
24. Hua, X, Nohturfft, A., Goldstein, J. L. & Brown, M. S. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87, 415-426 (1996). The important role of the sterol-sensing domain was established when SCAP was cloned based on the dominant sterol-resistant phenotype of a point mutant.
25. Nohturfft, A., Hua, X., Brown, M. S. & Goldstein, J. L. Recurrent G-to-A substitution in a single codon of SREBP cleavage-activating protein causes sterol resistance in three mutant Chinese hamster ovary cell lines. Proc. Natl Acad. Sci. USA 93, 13709-13714 (1996).
26. Yabe, D., Xia, Z. P., Adams, C. M. & Rawson, R. B. Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols. Proc. Natl Acad. Sci. USA 99, 16672-16677 (2002) Establishes a correlation between the dominant sterol-resistant phenotype of point mutations in the sterol-sensing domain of SCAP and the failure to interact with either Insig-1 or -2.
27. Neer, E. J., Schmidt, C. J., Nambudripad, R. & Smith, T. F. The ancient regulatory-protein family of WD-repeat proteins. Nature 371, 297-300 (1994).
28. Sakai, J. et al. Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J. Biol. Chem. 272, 20213-20221 (1997).
29. Sakai, J., Nohturfft, A., Goldstein, J. L. & Brown, M. S. Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies. J. Biol. Chem. 273, 5785-5793 (1998).
30. Rawson, R. B., DeBose-Boyd, R., Goldstein, J. L. & Brown, M. S. Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein. J. Biol. Chem. 274, 28549-28556 (1999).
31. Duncan, E. A., Brown, M. S., Goldstein, J. L. & Sakai, J. Cleavage site for sterol-regulated protease localized to a Leu-Ser bond in the lumenal loop of sterol regulatory element-binding protein-2. J. Biol. Chem. 272, 12778-12785 (1997).
32. Sakai, J. et al. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol. Cell 2, 505-514 (1998).
33. Seidah, N. G. et al. Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc. Natl Acad. Sci. USA 96, 1321-1326 (1999).
34. Espenshade, P. J., Cheng, D., Goldstein, J. L. & Brown, M. S. Autocatalytic processing of site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins. J. Biol. Chem. 274, 22795-22804 (1999).
35. Toure, B. B. et al. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J. Biol. Chem. 275, 2349-2358 (2000).
36. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787-3799 (1999).
37. Ye, J. et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355-1364 (2000).
38. Lenz, O., ter Meulen, J., Klenk, H. D., Seidah, N. G. & Garten, W. The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc. Natl Acad. Sci. USA 98, 12701-12705 (2001).
39. Beyer, W. R., Popplau, D., Garten, W., Von Laer, D. & Lenz, O. Endoproteolytic processing of the lymphocytic choriomeningitis virus glycoprotein by the subtilase SKI-1/S1P. J. Virol. 77, 2866-2872 (2003).
40. Sanchez, A. J., Vincent, M. J. & Nichol, S. T. Characterization of the glycoproteins of Crimean-Congo hemorrhagic fever virus. J. Virol. 76, 7263-7275 (2002).
41. Elagoz, A., Benjannet, S., Mammarbassi, A., Wickham, L. & Seidah, N. G. Biosynthesis and cellular trafficking of the convertase SKF1/S1P: ectodomain shedding requires SKI-1 activity. J. Biol. Chem. 277, 11265-11275 (2002).
42. Rawson, R. B., Cheng, D., Brown, M. S. & Goldstein, J. L. Isolation of cholesterol-requiring mutant Chinese hamster ovary cells with defects in cleavage of sterol regulatory element-binding proteins at site 1. J. Biol. Chem. 273, 28261-28269 (1998).
43. Rawson, R. B. et al. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol. Cell 1, 47-57 (1997).
44. Rawlings, N. D. & Barrett, A. J. Evolutionary families of metallopeptidases. Methods Enzymol. 248, 183-228 (1995),
45. Rawlings, N. D., O'Brien, E. & Barrett, A. J. MEROPS: the protease database. Nucleic Acids Res. 30, 343-346 (2002).
46. Hasan, M. T., Chang, C. C. & Chang, T. Y. Somatic cell genetic and biochemical characterization of cell lines resulting from human genomic DNA transfections of Chinese hamster ovary cell mutants defective in sterol-dependent activation of sterol synthesis and LDL receptor expression. Somat. Cell Mol. Genet. 20, 183-194 (1994).
47. Zelenski, N. G., Rawson, R. B., Brown, M. S. & Goldstein, J. L. Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins. J. Biol. Chem. 274, 21973-21980 (1999).
48. Lewis, A. P. & Thomas, P. J. A novel clan of zinc metallopeptidases with possible intramembrane cleavage properties. Protein Sci. 8, 439-442 (1999).
49. Yang, T., Goldstein, J. L. & Brown, M. S. Overexpression of membrane domain of SCAP prevents sterols from inhibiting SCAP:SREBP exit from endoplasmic reticulum. J. Biol. Chem. 275, 29881-29886 (2000). Establishes the existence of a separate protein required for the retention of SCAP-SREBP complexes in the ER.
50. Yang, T. et al. Crucial step in cholesterol homeostasis Sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER, Cell 110, 489-500 (2002). Identifies Insig-1 as a membrane-bound retention factor required to hold the SREBP-SCAP complex in the ER in the presence of sterols.
51. Yabe, D., Brown, M. S. & Goldstein, J. L. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc. Natl Acad. Sci. USA 99, 12753-12758 (2002). Shows that Insig-2 acts in a manner similar to Insig-1.
52. Diamond, R. H. et al. Novel delayed-early and highly insulin-induced growth response genes. Identification of HRS, a potential regulator of alternative pre-mRNA splicing. J. Biol. Chem. 268, 15185-15192 (1993).
53. Janowski, B. A. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP. Proc. Natl Acad. Sci. USA 99, 12675-12680 (2002).
54. Yabe, D., Komuro, R., Liang, G., Goldstein, J. L. & Brown, M. S. Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. Proc. Natl Acad. Sci. USA 100, 3155-3160 (2003). The experiments presented here indicate that the transcriptional regulation of Insig-2 by insulin might explain how insulin signalling upregulates fatty-acid synthesis in the liver.
55. Nohturfft, A., Brown, M. S. & Goldstein, J. L. Sterols regulate processing of carbohydrate chains of wild-type SREBP cleavage-activating protein (SCAP), but not sterol-resistant mutants Y298C or D443N. Proc. Natl Acad Sci. USA 95, 12848-12853 (1998).
56. Brown, A., Sun, L., Feramisco, J., Brown, M. & Goldstein, J. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell 10, 237-245 (2002). The authors report that SCAP undergoes a conformational change following the addition of sterols to vesicles in vitro.
57. Goldstein, J. L. & Brown, M. S. Regulation of the mevalonate pathway. Nature 343, 425-430 (1990).
58. Jingami, H., Brown, M. S., Goldstein, J. L., Anderson, R. G. & Luskey, K. L. Partial deletion of membrane-bound domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase eliminates sterol-enhanced degradation and prevents formation of crystalloid endoplasmic reticulum. J. Cell Biol. 104, 1693-1704 (1987).
59. Ravid, T., Doolman, R., Avner, R., Harats, D. & Roitelman, J. The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J. Biol. Chem. 275, 35840-35847 (2000).
60. Hampton, R. Y. & Bhakta, H. Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase. Proc. Natl Acad. Sci. USA 94, 12944-12948 (1997).
61. Gil, G., Faust, J. R., Chin, D. J., Goldstein, J. L. & Brown, M. S. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 41, 249-258 (1985).
62. Sever, N., Yang, T., Brown, M. S., Goldstein, J. L. & DeBose-Boyd, R. A. Accelerated degradation of HMG CoA reductase mediated by binding of Insig-1 to its sterol-sensing domain. Mol. Cell 11, 25-33 (2003). Identifies a role for Insig-1 in the regulation of the stability of HMG CoA reductase by interaction with its sterol-sensing domain.
63. Seegmiller, A. C. et al. The SREBP pathway in Drosophila: regulation by palmitate, not sterols. Dev. Cell 2, 229-238 (2002). Reports the regulation of dSREBP cleavage by fatty acids rather than sterols.
64. Holt, R. A. et al. The genome sequence of the malaria mosquito Anopheles gambiae. Science 298, 129-149 (2002)
65. Shimomura, I., Shimano, H., Korn, B. S., Bashmakov, Y. & Horton, J. D. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J. Biol. Chem. 273, 35299-35306 (1998).
66. Horton, J. D. & Shimomura, I. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr. Opin. Lipidol. 10, 143-150 (1999).
67. Lagace, T. A., Storey, M. K. & Ridgway, N. D. Regulation of phosphatidylcholine metabolism in Chinese hamster ovary cells by the sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein pathway. J. Biol. Chem. 275, 14367-14374 (2000).
68. Theopold, U., Ekengren, S. & Hultmark, D. HLH106, a Drosophila transcription factor with similarity to the vertebrate sterol responsive element binding protein. Proc. Natl Acad Sci. USA 93, 1195-1199 (1996).
69. Hannah, V. C., Ou, J., Luong, A., Goldstein, J. L. & Brown, M. S. Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells. J. Biol. Chem. 276, 4365-4372 (2001).
70. Worgall, T. S., Johnson, R. A., Seo, T., Gierens, H. & Deckelbaum, R. J. Unsaturated fatty acids mediated decreases in sterol regulatory element mediated gene transcription are linked to cell sphingolipid metabolism J. Biol. Chem. 277, 3878-3885 (2002).
71. Dobrosotskaya, I. Y., Seegmiller, A. C., Brown, M. S., Goldstein, J. L. & Rawson, R. B. Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science 296, 879-883 (2002). The first report of the role of phosphatidylethanolamine in the regulation of SREBP processing in insects.
72. Cullis, P. R. & Hope, M. J. in Biochemistry of Lipids and Membranes (eds Vance, D. E. & Vance, J. E.) 25-72 (Benjamin/Cummings, Menlo Park, California, 1985).
73. Voogt, P. A. & van Rheenen, J. W. On the sterols of some ascidians. Arch. Int. Physiol. Biochim. 83, 563-572 (1975).
74. McKay, R. M., McKay, J. P., Avery, L. & Graff, J. M. C. elegans. A model for exploring the genetics of fat storage. Dev. Cell 4, 131-142 (2003).
75. Carson, D. D. & Lennarz, W. J. Inhibition of polyisoprenoid and glycoprotein biosynthesis causes abnormal embryonic development. Proc. Natl Acad. Sci. USA 76, 5709-5713 (1979).
76. Hua, X., Sakai, J., Ho, Y. K., Goldstein, J. L. & Brown, M. S. Hairpin orientation of sterol regulatory element-binding protein-2 in cell membranes as determined by protease protection. J. Biol. Chem. 270, 29422-29427 (1995).
77. Nohturfft, A., DeBose-Boyd, R. A., Scheek, S., Goldstein, J. L. & Brown, M. S. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi. Proc. Natl Acad. USA 96, 11235-11240 (1999).
78. DeBose-Boyd, R. A. et al. 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).
79. Duncan, E. A., Dave, U. P., Sakai, J., Goldstein, J. L. & Brown, M. S. Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning. J. Biol. Chem. 273, 17801-17809 (1998).
80. Nohturfft, A., Brown, M. S. & Goldstein, J. L. Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J. Biol. Chem. 273, 17243-17250 (1998).
81. Clark, A. J. & Bloch, K. Absence of sterol biosynthesis in insects. J. Biol. Chem. 234, 2578-2588 (1959).