102
Views
26
CrossRef citations to date
0
Altmetric
Article

A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

, , , , , , , , & show all
Pages 285-294 | Received 22 Sep 2015, Accepted 27 Oct 2015, Published online: 17 Mar 2023

REFERENCES

  • Maxfield FR, van Meer G. 2010. Cholesterol, the central lipid of mammalian cells. Curr Opin Cell Biol 22:422–429. http://dx.doi.org/10.1016/j.ceb.2010.05.004.
  • Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS. 1993. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75:187–197. http://dx.doi.org/10.1016/S0092-8674(05)80095-9.
  • Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, Wang X. 1993. 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 U S A 90:11603–11607. http://dx.doi.org/10.1073/pnas.90.24.11603.
  • Horton JD, Goldstein JL, Brown MS. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125–1131. http://dx.doi.org/10.1172/JCI0215593.
  • Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ. 1998. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693–704. http://dx.doi.org/10.1016/S0092-8674(00)81432-4.
  • Zelcer N, Tontonoz P. 2006. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607–614. http://dx.doi.org/10.1172/JCI27883.
  • Goldstein JL, DeBose-Boyd RA, Brown MS. 2006. Protein sensors for membrane sterols. Cell 124:35–46. http://dx.doi.org/10.1016/j.cell.2005.12.022.
  • Brown MS, Goldstein JL. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47. http://dx.doi.org/10.1126/science.3513311.
  • Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. 1996. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383:728–731. http://dx.doi.org/10.1038/383728a0.
  • Zelcer N, Hong C, Boyadjian R, Tontonoz P. 2009. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325:100–104. http://dx.doi.org/10.1126/science.1168974.
  • Sharpe LJ, Brown AJ. 2013. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem 288:18707–18715. http://dx.doi.org/10.1074/jbc.R113.479808.
  • Jo Y, DeBose-Boyd RA. 2010. Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase. Crit Rev Biochem Mol Biol 45:185–198. http://dx.doi.org/10.3109/10409238.2010.485605.
  • Song B-L, Sever N, DeBose-Boyd RA. 2005. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell 19:829–840. http://dx.doi.org/10.1016/j.molcel.2005.08.009.
  • Jo Y, Lee PCW, Sguigna PV, DeBose-Boyd RA. 2011. Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8. Proc Natl Acad Sci U S A 108:20503–20508. http://dx.doi.org/10.1073/pnas.1112831108.
  • Gill S, Stevenson J, Kristiana I, Brown AJ. 2011. Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase. Cell Metab 13:260–273. http://dx.doi.org/10.1016/j.cmet.2011.01.015.
  • Zelcer N, Sharpe LJ, Loregger A, Kristiana I, Cook ECL, Phan L, Stevenson J, Brown AJ. 2014. The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway. Mol Cell Biol 34:1262–1270. http://dx.doi.org/10.1128/MCB.01140-13.
  • Foresti O, Ruggiano A, Hannibal-Bach HK, Ejsing CS, Carvalho P. 2013. Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. eLife 2:e00953. http://dx.doi.org/10.7554/eLife.00953.
  • Sharpe LJ, Cook ECL, Zelcer N, Brown AJ. 2014. The UPS and downs of cholesterol homeostasis. Trends Biochem Sci 39:527–535. http://dx.doi.org/10.1016/j.tibs.2014.08.008.
  • Kikkert M, Doolman R, Dai M, Avner R, Hassink G, van Voorden S, Thanedar S, Roitelman J, Chau V, Wiertz E. 2004. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J Biol Chem 279:3525–3534.
  • Schippers IJ, Moshage H, Roelofsen H, Müller M, Heymans HS, Ruiters M, Kuipers F. 1997. Immortalized human hepatocytes as a tool for the study of hepatocytic (de-)differentiation. Cell Biol Toxicol 13:375–386. http://dx.doi.org/10.1023/A:1007404028681.
  • Yamaguchi S, Yamane T, Takahashi-Niki K, Kato I, Niki T, Goldberg MS, Shen J, Ishimoto K, Doi T, Iguchi-Ariga SMM, Ariga H. 2012. Transcriptional activation of low-density lipoprotein receptor gene by DJ-1 and effect of DJ-1 on cholesterol homeostasis. PLoS One 7:e38144. http://dx.doi.org/10.1371/journal.pone.0038144.
  • Kang Y-L, Yochem J, Bell L, Sorensen EB, Chen L, Conner SD. 2013. Caenorhabditis elegans reveals a FxNPxY-independent LDLR internalization mechanism mediated by Epsin1. Mol Biol Cell 24:308–318. http://dx.doi.org/10.1091/mbc.E12-02-0163.
  • Lambert G, Petrides F, Chatelais M, Blom DJ, Choque B, Tabet F, Wong G, Rye K-A, Hooper AJ, Burnett JR, Barter PJ, Marais AD. 2014. Elevated plasma PCSK9 level is equally detrimental for patients with nonfamilial hypercholesterolemia and heterozygous familial hypercholesterolemia, irrespective of low-density lipoprotein receptor defects. J Am Coll Cardiol 63:2365–2373. http://dx.doi.org/10.1016/j.jacc.2014.02.538.
  • Motazacker MM, Pirruccello J, Huijgen R, Do R, Gabriel S, Peter J, Kuivenhoven JA, Defesche JC, Kastelein JJP, Hovingh GK, Zelcer N, Kathiresan S, Fouchier SW. 2012. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur Heart J 33:1360–1366. http://dx.doi.org/10.1093/eurheartj/ehs010.
  • Wang X, Briggs MR, Hua X, Yokoyama C, Goldstein JL, Brown MS. 1993. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. J Biol Chem 268:14497–14504.
  • Maxwell KN, Fisher EA, Breslow JL. 2005. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A 102:2069–2074. http://dx.doi.org/10.1073/pnas.0409736102.
  • Wang Y, Huang Y, Hobbs HH, Cohen JC. 2012. Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res 53:1932–1943. http://dx.doi.org/10.1194/jlr.M028563.
  • Sorrentino V, Nelson JK, Maspero E, Marques ARA, Scheer L, Polo S, Zelcer N. 2013. The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation. J Lipid Res 54:2174–2184. http://dx.doi.org/10.1194/jlr.M037713.
  • Seidah NG. 2009. PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets 13:19–28. http://dx.doi.org/10.1517/14728220802600715.
  • Jeong HJ, Lee H-S, Kim K-S, Kim Y-K, Yoon D, Park SW. 2008. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res 49:399–409.
  • Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A. 2004. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24:1454–1459. http://dx.doi.org/10.1161/01.ATV.0000134621.14315.43.
  • Lambert G, Chatelais M, Petrides F, Passard M, Thedrez A, Rye K-A, Schwahn U, Gusarova V, Blom DJ, Sasiela W, Marais AD. 2014. Normalization of low-density lipoprotein receptor expression in receptor defective homozygous familial hypercholesterolemia by inhibition of PCSK9 with alirocumab. J Am Coll Cardiol 64:2299–2300. http://dx.doi.org/10.1016/j.jacc.2014.07.995.
  • Scotti E, Calamai M, Goulbourne CN, Zhang L, Hong C, Lin RR, Choi J, Pilch PF, Fong LG, Zou P, Ting AY, Pavone FS, Young SG, Tontonoz P. 2013. IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor. Mol Cell Biol 33:1503–1514. http://dx.doi.org/10.1128/MCB.01716-12.
  • Sorrentino V, Zelcer N. 2012. Post-transcriptional regulation of lipoprotein receptors by the E3-ubiquitin ligase inducible degrader of the low-density lipoprotein receptor. Curr Opin Lipidol 23:213–219. http://dx.doi.org/10.1097/MOL.0b013e3283532947.
  • Hong C, Duit S, Jalonen P, Out R, Scheer L, Sorrentino V, Boyadjian R, Rodenburg KW, Foley E, Korhonen L, Lindholm D, Nimpf J, van Berkel TJC, Tontonoz P, Zelcer N. 2010. The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. J Biol Chem 285:19720–19726. http://dx.doi.org/10.1074/jbc.M110.123729.
  • Hassink G, Kikkert M, van Voorden S, Lee S-J, Spaapen R, van Laar T, Coleman CS, Bartee E, Früh K, Chau V, Wiertz E. 2005. TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem J 388:647–655. http://dx.doi.org/10.1042/BJ20041241.
  • Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P. 2008. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111. http://dx.doi.org/10.1016/j.cell.2008.04.052.
  • Yang C, McDonald JG, Patel A, Zhang Y, Umetani M, Xu F, Westover EJ, Covey DF, Mangelsdorf DJ, Cohen JC, Hobbs HH. 2006. Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem 281:27816–27826. http://dx.doi.org/10.1074/jbc.M603781200.
  • Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, Reichart D, Fox JN, Shaked I, Heudobler D, Raetz CRH, Wang EW, Kelly SL, Sullards MC, Murphy RC, Merrill AH, Brown HA, Dennis EA, Li AC, Ley K, Tsimikas S, Fahy E, Subramaniam S, Quehenberger O, Russell DW, Glass CK. 2012. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151:138–152. http://dx.doi.org/10.1016/j.cell.2012.06.054.
  • Wong J, Quinn CM, Brown AJ. 2004. Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol 24:2365–2371. http://dx.doi.org/10.1161/01.ATV.0000148707.93054.7d.
  • Sasaki M, Terao Y, Ayaori M, Uto-Kondo H, Iizuka M, Yogo M, Hagisawa K, Takiguchi S, Yakushiji E, Nakaya K, Ogura M, Komatsu T, Ikewaki K. 2014. Hepatic overexpression of idol increases circulating protein convertase subtilisin/kexin type 9 in mice and hamsters via dual mechanisms: sterol regulatory element-binding protein 2 and low-density lipoprotein receptor-dependent pathways. Arterioscler Thromb Vasc Biol 34:1171–1178. http://dx.doi.org/10.1161/ATVBAHA.113.302670.
  • Hong C, Marshall SM, McDaniel AL, Graham M, Layne JD, Cai L, Scotti E, Boyadjian R, Kim J, Chamberlain BT, Tangirala RK, Jung ME, Fong L, Lee R, Young SG, Temel RE, Tontonoz P. 2014. The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab 20:910–918. http://dx.doi.org/10.1016/j.cmet.2014.10.001.
  • Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee J-Y, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RYL, Wright AF, Witteman JC, Wilson JF, et al.. 2010. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466:707–713. http://dx.doi.org/10.1038/nature09270.
  • Sorrentino V, Fouchier SW, Motazacker MM, Nelson JK, Defesche JC, Dallinga-Thie GM, Kastelein JJP, Kees Hovingh G, Zelcer N. 2013. Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein. Eur Heart J 34:1292–1297. http://dx.doi.org/10.1093/eurheartj/ehs472.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.