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The SREBP pathway — insights from insigs and insects
Nature Reviews Molecular Cell Biologyvolume 4, pages631–640 (2003)Cite this article
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Key Points
The SREBPs (sterol regulatory element binding proteins) are membrane-bound transcription factors that control lipid synthesis in animal cells. The transcriptionally active amino terminus is released from the membrane following two sequential proteolytic steps that are carried out by S1P and S2P.
Lipids control the release of active SREBP by regulating the access of the precursor protein, which is located in the endoplasmic reticulum (ER), to the proteases, S1P and S2P, which are found in the Golgi apparatus.
Movement of SREBP from the ER to the Golgi requires an escort factor, known as SCAP (SREBP-cleavage-activating protein). The amino-terminal half of SCAP consists of eight membrane-spanning helices, of which helices 2–6 comprise the sterol-sensing domain. SREBP and SCAP form a complex that is stable in both the presence and the absence of sterols. The SCAP's sterol-sensing domain is essential for transducing signals from cellular lipid concentrations to transport SREBP from the ER to the Golgi.
Two recently identified proteins, Insig-1 and Insig-2, are required for the sterol-mediated regulation of SCAP–SREBP movement. Point mutations within the SCAP sterol-sensing domain abolish sterol-mediated regulation and block the interaction between SCAP and Insig-1 or Insig-2. Insig-1 also interacts with the sterol-sensing domain of HMG CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, to regulate its stability.
Insects have all the known components of the SREBP pathway, except for the Insig proteins. Processing of SREBP in insects is regulated by phosphatidylethanolamine, rather than by sterols.
The suppressive action of two such different lipids on SREBP processing indicates that SCAP might sense physical properties of the membrane rather than interact with lipids in a classic receptor–ligand fashion.
Abstract
Animal cells coordinate lipid homeostasis by end-product feedback regulation of transcription. The control occurs through the proteolytic release of transcriptionally active sterol regulatory element binding proteins (SREBPs) from intracellular membranes. This feedback system has unexpected features that are found in all cells. Here, we consider recently discovered components of the regulatory machinery that govern SREBP processing, as well as studies inDrosophila that indicate an ancient role for the SREBP pathway in integrating membrane composition and lipid biosynthesis.
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References
Brown, M. S., Ye, J., Rawson, R. B. & Goldstein, J. L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.Cell100, 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.
Brown, M. S. & Goldstein, J. L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood.Proc. Natl Acad. Sci. USA96, 11041–11048 (1999).
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.Cell102, 315–323 (2000).
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. USA99, 11694–11699 (2002).
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).
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).
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).
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).
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.
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.Cell48, 1061–1069 (1987).
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).
Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.Cell89, 331–340 (1997).
Yokoyama, C. et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene.Cell75, 187–197 (1993).
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. USA90, 11603–11607 (1993).
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).
Wang, X., Sato, R., Brown, M. S., Hua, X. & Goldstein, J. L. SREBP-1, a membrane-bound transcription factor released by sterol- regulated proteolysis.Cell77, 53–62 (1994).Describes the sterol-regulated proteolysis of SREBP.
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).
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).
Shimano, H. et al. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.J. Clin. Invest.99, 846–854 (1997).
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).
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).
Carstea, E. D. et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.Science277, 228–231 (1997).
Loftus, S. K. et al. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science277, 232–235 (1997).
Hua, X., Nohturfft, A., Goldstein, J. L. & Brown, M. S. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein.Cell87, 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.
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. USA93, 13709–13714 (1996).
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. USA99, 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.
Neer, E. J., Schmidt, C. J., Nambudripad, R. & Smith, T. F. The ancient regulatory-protein family of WD-repeat proteins.Nature371, 297–300 (1994).
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).
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 fromin vivo competition studies.J. Biol. Chem.273, 5785–5793 (1998).
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).
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).
Sakai, J. et al. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells.Mol. Cell2, 505–514 (1998).
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. USA96, 1321–1326 (1999).
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).
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).
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. Cell10, 3787–3799 (1999).
Ye, J. et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.Mol. Cell6, 1355–1364 (2000).
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. USA98, 12701–12705 (2001).
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).
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).
Elagoz, A., Benjannet, S., Mammarbassi, A., Wickham, L. & Seidah, N. G. Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity.J. Biol. Chem.277, 11265–11275 (2002).
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).
Rawson, R. B. et al. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.Mol. Cell1, 47–57 (1997).
Rawlings, N. D. & Barrett, A. J. Evolutionary families of metallopeptidases.Methods Enzymol.248, 183–228 (1995).
Rawlings, N. D., O'Brien, E. & Barrett, A. J. MEROPS: the protease database.Nucleic Acids Res.30, 343–346 (2002).
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).
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).
Lewis, A. P. & Thomas, P. J. A novel clan of zinc metallopeptidases with possible intramembrane cleavage properties.Protein Sci.8, 439–442 (1999).
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.
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.Cell110, 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.
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. USA99, 12753–12758 (2002).Shows that Insig-2 acts in a manner similar to Insig-1.
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).
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. USA99, 12675–12680 (2002).
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. USA100, 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.
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. USA95, 12848–12853 (1998).
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. Cell10, 237–245 (2002).The authors report that SCAP undergoes a conformational change following the addition of sterols to vesiclesin vitro.
Goldstein, J. L. & Brown, M. S. Regulation of the mevalonate pathway.Nature343, 425–430 (1990).
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).
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).
Hampton, R. Y. & Bhakta, H. Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase.Proc. Natl Acad. Sci. USA94, 12944–12948 (1997).
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.Cell41, 249–258 (1985).
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. Cell11, 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.
Seegmiller, A. C. et al. The SREBP pathway inDrosophila: regulation by palmitate, not sterols.Dev. Cell2, 229–238 (2002).Reports the regulation of dSREBP cleavage by fatty acids rather than sterols.
Holt, R. A. et al. The genome sequence of the malaria mosquitoAnopheles gambiae.Science298, 129–149 (2002).
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).
Horton, J. D. & Shimomura, I. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis.Curr. Opin. Lipidol.10, 143–150 (1999).
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).
Theopold, U., Ekengren, S. & Hultmark, D.HLH106, aDrosophila transcription factor with similarity to the vertebrate sterol responsive element binding protein.Proc. Natl Acad. Sci. USA93, 1195–1199 (1996).
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).
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).
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 inDrosophila.Science296, 879–883 (2002).The first report of the role of phosphatidylethanolamine in the regulation of SREBP processing in insects.
Cullis, P. R. & Hope, M. J. inBiochemistry of Lipids and Membranes (eds Vance, D. E. & Vance, J. E.) 25–72 (Benjamin/Cummings, Menlo Park, California, 1985).
Voogt, P. A. & van Rheenen, J. W. On the sterols of some ascidians.Arch. Int. Physiol. Biochim.83, 563–572 (1975).
McKay, R. M., McKay, J. P., Avery, L. & Graff, J. M.C. elegans. A model for exploring the genetics of fat storage.Dev. Cell4, 131–142 (2003).
Carson, D. D. & Lennarz, W. J. Inhibition of polyisoprenoid and glycoprotein biosynthesis causes abnormal embryonic development.Proc. Natl Acad. Sci. USA76, 5709–5713 (1979).
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).
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. Sci. USA96, 11235–11240 (1999).
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.Cell99, 703–712 (1999).
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).
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).
Clark, A. J. & Bloch, K. Absence of sterol biosynthesis in insects.J. Biol. Chem.234, 2578–2588 (1959).
Acknowledgements
I am grateful to R. A. DeBose-Boyd, J. D. Horton and members of the Rawson laboratory for comments on this manuscript. This work is supported by grants from the American Heart Association, the National Institutes of Health and the Perot Family Foundation.
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Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA
Robert B. Rawson
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Glossary
- SREBP
(Sterol regulatory element binding protein). A transcription factor in animal cells that is necessary for the transcriptional activation of genes required for lipid synthesis.
- RIP
(Regulated intramembrane proteolysis). The cleavage of a protein within a membrane-spanning helix to release a functional domain. This cleavage usually follows an initial, regulated cleavage that occurs in the extracytoplasmic domain of the substrate.
- S1P
(Site-1 protease). A membrane-anchored subtilisin-like serine protease of the secretory pathway, the active site of which is in the lumen.
- S2P
(Site-2 protease). An unusually hydrophobic metalloproteinase that cleaves its substrates within membrane-spanning helices.
- SCAP
(SREBP-cleavage-activating protein). A large, polytopic membrane protein that senses cellular sterol concentrations and escorts SREBP from the ER to the Golgi apparatus.
- COPII
Coatamer protein complex II, which is required for intracellular vesicle formation.
- INSIG
A membrane protein of the endoplasmic reticulum (ER) that interacts with the sterol-sensing domain of SCAP and serves to retain the SCAP–SREBP complexes within the ER.
- HMG CoA
(3-hydroxy-3-methylglutaryl coenzyme A). The activated species that is reduced to form mevalonate, the precursor of cholesterol and isoprenoid compounds.
- STEROL-SENSING DOMAIN
A motif of five transmembrane helices that is found in SCAP and HMG CoA reductase where it mediates protein movement or stability through interaction with the Insig proteins. Similar domains are present in other proteins associated with cholesterol metabolism, such as the Niemann–Pick C disease protein and the Hedgehog receptor, Patched.
- UNFOLDED PROTEIN RESPONSE
An intracellular signalling pathway that connects the endoplasmic reticulum (ER) with the nucleus. Under stress conditions (when unfolded proteins accumulate in the ER), cells react by the increased transcription of chaperone genes. These chaperones are required for the maintenance of protein folding.
- ER STRESS
A cellular response to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). Although a normal physiological phenomenon, it can also be provoked by several conditions, such as viral infections and mutations that impair protein folding.
- MEVALONATE PATHWAY
The series of enzymes, and the reactions they catalyse, that convert acetyl coenzyme A to many different hydrophobic products such as farnesol, geranylgeranol, dolichol, and, in vertebrate animals, cholesterol.
- RNAi
RNA-mediated interference of gene expression. The process whereby the introduction of double-stranded RNA into a cell elicits a response that catalytically destroys single-stranded RNAs that contain the cognate sequence.
- PHOSPHATIDYLETHANOLAMINE
A phospholipid with the unusually small headgroup ethanolamine attached to its diacylglycerol backbone.
- HII PHASE
Lipids that form tubular structures following hydration, wherein the hydrophilic moieties are facing the inner surface of a tube, and the hydrophobic moieties face outward. As a result, multiple tubes associate through hydrophobic interactions, yielding a structure that seems hexagonal in cross section.
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Rawson, R. The SREBP pathway — insights from insigs and insects.Nat Rev Mol Cell Biol4, 631–640 (2003). https://doi.org/10.1038/nrm1174
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