دورية أكاديمية
أعرض في EDS

Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.

التفاصيل البيبلوغرافية
العنوان: Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.
المؤلفون: Coates HW; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia., Capell-Hattam IM; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia., Olzomer EM; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia., Du X; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia., Farrell R; Prince of Wales Private Hospital, Randwick, Australia.; Chris O'Brien Lifehouse, Camperdown, Australia., Yang H; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia., Byrne FL; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia., Brown AJ; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, Australia.
المصدر: ELife [Elife] 2023 Jan 19; Vol. 12. Date of Electronic Publication: 2023 Jan 19.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Squalene Monooxygenase*/genetics , Squalene Monooxygenase*/chemistry , Squalene Monooxygenase*/metabolism , Cholesterol*/metabolism, Humans ; Squalene ; Hypoxia ; Oxygen
مستخلص: Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.
Competing Interests: HC, IC, EO, XD, RF, HY, FB, AB No competing interests declared
(© 2023, Coates et al.)
References: Cancer Res. 2016 Aug 15;76(16):4785-90. (PMID: 27325648)
Cancer Res. 2022 Apr 1;82(7):1298-1312. (PMID: 35045984)
Elife. 2019 Sep 10;8:. (PMID: 31500697)
FASEB J. 2019 Jul;33(7):7929-7941. (PMID: 30917010)
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Nov;1864(11):1656-1668. (PMID: 31422115)
Sci Transl Med. 2018 Apr 18;10(437):. (PMID: 29669855)
Cancer Commun (Lond). 2021 Aug;41(8):726-746. (PMID: 34268906)
Genome Biol. 2016 Jun 29;17(1):140. (PMID: 27358048)
Nat Protoc. 2013 Nov;8(11):2281-2308. (PMID: 24157548)
Nat Commun. 2020 Sep 21;11(1):4755. (PMID: 32958772)
J Lipid Res. 1982 Mar;23(3):466-73. (PMID: 7200504)
J Lipid Res. 1995 Jan;36(1):67-79. (PMID: 7706949)
J Lipid Res. 2011 Jan;52(1):6-34. (PMID: 20929975)
Mol Cell Biol. 2009 May;29(10):2570-81. (PMID: 19273585)
Mol Cell Biol. 2014 Apr;34(7):1262-70. (PMID: 24449766)
Science. 2016 Apr 8;352(6282):175-80. (PMID: 27124451)
Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20. (PMID: 25514926)
Gastroenterology. 2021 Jun;160(7):2467-2482.e3. (PMID: 33647280)
Cancer Res. 2016 Apr 15;76(8):2063-70. (PMID: 27197250)
Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7150-7158. (PMID: 32170014)
Nat Cell Biol. 2022 Aug;24(8):1239-1251. (PMID: 35941365)
J Lipid Res. 1976 Jan;17(1):38-45. (PMID: 1255019)
Prog Lipid Res. 2020 Jul;79:101033. (PMID: 32360125)
J Biol Chem. 2007 Sep 14;282(37):27436-27446. (PMID: 17635920)
J Biol Chem. 2019 May 17;294(20):8134-8147. (PMID: 30940729)
Elife. 2013 Jul 23;2:e00953. (PMID: 23898401)
Cell Metab. 2011 Mar 2;13(3):260-73. (PMID: 21356516)
Circ Res. 2011 Oct 28;109(10):1141-52. (PMID: 21921268)
Cell Physiol Biochem. 2014;34(5):1427-41. (PMID: 25323790)
Nat Commun. 2019 Jan 9;10(1):97. (PMID: 30626872)
J Lipid Res. 2022 Dec;63(12):100295. (PMID: 36216146)
Methods Enzymol. 1983;98:241-60. (PMID: 6321901)
Mol Cancer Res. 2014 May;12(5):728-41. (PMID: 24523299)
Biochem J. 2020 Jan 31;477(2):541-555. (PMID: 31904814)
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32. (PMID: 14512514)
Nat Commun. 2021 Aug 20;12(1):5066. (PMID: 34417456)
J Biol Chem. 2017 Dec 8;292(49):19959-19973. (PMID: 28972164)
Gastroenterology. 2021 Mar;160(4):1194-1207.e28. (PMID: 32946903)
Mol Cell. 2006 Feb 17;21(4):521-31. (PMID: 16483933)
J Leukoc Biol. 2011 Sep;90(3):551-62. (PMID: 21685248)
Biochem Biophys Res Commun. 2007 Jan 5;352(1):259-63. (PMID: 17112472)
Biochem Biophys Res Commun. 1992 May 29;185(1):323-9. (PMID: 1599468)
Nat Protoc. 2008;3(6):1101-8. (PMID: 18546601)
Science. 2001 Apr 20;292(5516):464-8. (PMID: 11292862)
J Biol Chem. 2021 Jan-Jun;296:100731. (PMID: 33933449)
Sci Rep. 2016 Jan 18;6:19435. (PMID: 26777065)
J Biol Chem. 2015 Nov 13;290(46):27533-44. (PMID: 26434806)
PLoS One. 2015 Jan 29;10(1):e0116740. (PMID: 25633823)
J Biol Chem. 2008 Jan 11;283(2):700-7. (PMID: 17981807)
Biochim Biophys Acta. 2002 Dec 2;1556(2-3):149-54. (PMID: 12460672)
Curr Opin Lipidol. 2013 Oct;24(5):393-400. (PMID: 23942270)
Cancer Res. 2016 Aug 1;76(15):4430-42. (PMID: 27280394)
Nat Commun. 2019 Jan 9;10(1):96. (PMID: 30626880)
Lipids Health Dis. 2021 Jun 2;20(1):58. (PMID: 34078402)
Lipids Health Dis. 2007 Apr 05;6:10. (PMID: 17408498)
J Lipid Res. 2014 Mar;55(3):431-42. (PMID: 24353279)
Nucleic Acids Res. 2019 Jul 2;47(W1):W171-W174. (PMID: 31106371)
EMBO J. 2005 Oct 5;24(19):3470-81. (PMID: 16148948)
J Biol Chem. 2019 Feb 15;294(7):2436-2448. (PMID: 30545937)
J Cell Physiol. 2009 Jan;218(1):167-74. (PMID: 18781596)
PLoS One. 2013 Dec 23;8(12):e83888. (PMID: 24376768)
Front Genet. 2021 Jan 21;11:613162. (PMID: 33552133)
Arteriosclerosis. 1990 Jan-Feb;10(1):106-10. (PMID: 2297340)
Oncogene. 2001 Nov 15;20(52):7624-34. (PMID: 11753640)
Biochem Biophys Res Commun. 2007 Mar 2;354(1):148-53. (PMID: 17207770)
Lancet. 2010 Nov 13;376(9753):1670-81. (PMID: 21067804)
Br J Radiol. 2014 Mar;87(1035):20130676. (PMID: 24588669)
فهرسة مساهمة: Keywords: Cholesterol; Hypoxia; Squalene monooxygenase; biochemistry; chemical biology; human; proteasome; protein degradation
Local Abstract: [plain-language-summary] Cells need cholesterol to work properly but too much cholesterol is harmful and can contribute to atherosclerosis (narrowing of blood vessels), cancer and other diseases. Cells therefore carefully control the activity of the enzymes that are involved in making cholesterol, including an enzyme known as squalene monooxygenase. When the level of cholesterol in a cell rises, a protein called MARCHF6 adds molecules of ubiquitin to squalene monooxygenase. These molecules act as tags that direct the enzyme to be destroyed by a machine inside cells, known as the proteasome, thereby preventing further (unnecessary) production of cholesterol. Previous studies found that squalene monooxygenase is sometimes only partially broken down to make a shorter (truncated) form of the enzyme that is permanently active, even when the level of cholesterol in the cell is high. However, it was unclear what triggers this partial breakdown. The process of making cholesterol uses a lot of oxygen, yet many cancer cells thrive in tumours with low levels of oxygen. Here, Coates et al. used biochemical and cell biology approaches to study the effect of low oxygen levels on the activity of squalene monooxygenase in human cells. The experiments revealed that low oxygen levels trigger squalene monooxygenase to be partially degraded to make the truncated form of the enzyme. Firstly, MARCHF6 accumulates and adds ubiquitin to the enzyme to accelerate its delivery to the proteasome. Secondly, as the proteasome starts to degrade the enzyme, a build-up of squalene molecules impedes further breakdown of the enzyme. This mechanism preserves squalene monooxygenase activity when oxygen levels drop in cells, which may compensate for temporary oxygen shortfalls and allow cells to continue to make cholesterol. Squalene monooxygenase is overactive in individuals with a wide variety of diseases including fatty liver and prostate cancer. Drugs that block squalene monooxygenase activity have been shown to stop cancer cells from growing, but unfortunately these drugs are also toxic to mammals. These findings suggest that reducing the activity of squalene monooxygenase in more subtle ways, such as stopping it from being partially degraded, may be a more viable treatment strategy for cancer and other diseases associated with high levels of cholesterol.
المشرفين على المادة: EC 1.14.14.17 (Squalene Monooxygenase)
97C5T2UQ7J (Cholesterol)
7QWM220FJH (Squalene)
S88TT14065 (Oxygen)
تواريخ الأحداث: Date Created: 20230119 Date Completed: 20230123 Latest Revision: 20230322
رمز التحديث: 20230322
مُعرف محوري في PubMed: PMC9851614
DOI: 10.7554/eLife.82843
PMID: 36655986
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.82843