Glutamine sensing licenses cholesterol synthesis.
Cholesterol
HMGCR
MFN2
Nutrient Sensing
SREBP2
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
21 Oct 2024
21 Oct 2024
Historique:
received:
26
02
2024
accepted:
20
09
2024
revised:
11
09
2024
medline:
22
10
2024
pubmed:
22
10
2024
entrez:
21
10
2024
Statut:
aheadofprint
Résumé
The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.
Identifiants
pubmed: 39433901
doi: 10.1038/s44318-024-00269-0
pii: 10.1038/s44318-024-00269-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : EC | European Research Council (ERC)
ID : ERC-StG-2019 852457
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : Project ID 269925409
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 411422114-GRK 2550
Organisme : Netherlands Organization for Scientific Research
ID : NWO; 016.176.643
Organisme : Netherlands Organization for Scientific Research
ID : M.22.034; GENESIS
Organisme : Howard Hughes Medical Institute (HHMI)
ID : N/A
Informations de copyright
© 2024. The Author(s).
Références
Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917
pubmed: 13671378
doi: 10.1139/y59-099
Boncompain G, Divoux S, Gareil N, de Forges H, Lescure A, Latreche L, Mercanti V, Jollivet F, Raposo G, Perez F (2012) Synchronization of secretory protein traffic in populations of cells. Nat Methods 9:493–498
pubmed: 22406856
doi: 10.1038/nmeth.1928
Bray NL, Pimentel H, Melsted P, Pachter L (2016) Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol 34:525–527
pubmed: 27043002
doi: 10.1038/nbt.3519
Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340
pubmed: 9150132
doi: 10.1016/S0092-8674(00)80213-5
Brown MS, Radhakrishnan A, Goldstein JL (2018) Retrospective on cholesterol homeostasis: the central role of scap. Annu Rev Biochem 87:783–807
pubmed: 28841344
doi: 10.1146/annurev-biochem-062917-011852
Capel E, Vatier C, Cervera P, Stojkovic T, Disse E, Cottereau AS, Auclair M, Verpont MC, Mosbah H, Gourdy P et al (2018) MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue. J Clin Lipidol 12:1420–1435
pubmed: 30158064
doi: 10.1016/j.jacl.2018.07.009
Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562
pubmed: 17693261
doi: 10.1016/j.cell.2007.06.026
Chen Q, Kirk K, Shurubor YI, Zhao D, Arreguin AJ, Shahi I, Valsecchi F, Primiano G, Calder EL, Carelli V et al (2018) Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab 27:1007–1025.e1005
pubmed: 29657030
pmcid: 5932217
doi: 10.1016/j.cmet.2018.03.002
Chen R, Zou Y, Mao D, Sun D, Gao G, Shi J, Liu X, Zhu C, Yang M, Ye W et al (2014) The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation. J Cell Biol 206:173–182
pubmed: 25049270
pmcid: 4107793
doi: 10.1083/jcb.201403009
Cheng C, Geng F, Li Z, Zhong Y, Wang H, Cheng X, Zhao Y, Mo X, Horbinski C, Duan W et al (2022) Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth. Nat Metab 4:575–588
pubmed: 35534729
pmcid: 9177652
doi: 10.1038/s42255-022-00568-y
Cheng C, Guo JY, Geng F, Wu X, Cheng X, Li Q, Guo D (2016) Analysis of SCAP N-glycosylation and trafficking in human cells. J Vis Exp 54709. https://doi.org/10.3791/54709
Clarke PR, Hardie DG (1990) Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J 9:2439–2446
pubmed: 2369897
pmcid: 552270
doi: 10.1002/j.1460-2075.1990.tb07420.x
Coleman PS, Parlo RA (2021) Warburg’s ghost-cancer’s self-sustaining phenotype: the aberrant carbon flux in cholesterol-enriched tumor mitochondria via deregulated cholesterogenesis. Front Cell Dev Biol 9:626316
pubmed: 33777935
pmcid: 7994618
doi: 10.3389/fcell.2021.626316
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350
pubmed: 18032601
pmcid: 2148292
doi: 10.1073/pnas.0709747104
DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ (1999) 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
pubmed: 10619424
doi: 10.1016/S0092-8674(00)81668-2
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361
pubmed: 20428172
pmcid: 2946640
doi: 10.1038/nature08938
Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN (2012) Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 47:349–358
pubmed: 22749528
doi: 10.1016/j.molcel.2012.05.043
Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S et al (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171–183
pubmed: 20670887
pmcid: 2946786
doi: 10.1016/j.molcel.2010.06.022
Eagle H, Oyama VI, Levy M, Horton CL, Fleischman R (1956) The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. J Biol Chem 218:607–616
pubmed: 13295214
doi: 10.1016/S0021-9258(18)65826-0
Edwards-Hicks, J, Mitterer M, Pearce EL, Buescher JM (2020) Metabolic Dynamics of In Vitro CD8+ T Cell Activation. Metabolites 11:12
Espenshade PJ, Li WP, Yabe D (2002) Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc Natl Acad Sci USA 99:11694–11699
pubmed: 12193656
pmcid: 129331
doi: 10.1073/pnas.182412799
George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernandez-Cuesta L, Bosco G et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524:47–53
pubmed: 26168399
pmcid: 4861069
doi: 10.1038/nature14664
Ghoddoussi F, Galloway MP, Jambekar A, Bame M, Needleman R, Brusilow WS (2010) Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS. J Neurol Sci 290:41–47
pubmed: 20060132
doi: 10.1016/j.jns.2009.11.013
Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430
pubmed: 1967820
doi: 10.1038/343425a0
Herzig S, Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19:121–135
pubmed: 28974774
doi: 10.1038/nrm.2017.95
Hua X, Nohturfft A, Goldstein JL, Brown MS (1996) Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87:415–426
pubmed: 8898195
doi: 10.1016/S0092-8674(00)81362-8
Inoue J, Ito Y, Shimada S, Satoh SI, Sasaki T, Hashidume T, Kamoshida Y, Shimizu M, Sato R (2011) Glutamine stimulates the gene expression and processing of sterol regulatory element binding proteins, thereby increasing the expression of their target genes. FEBS J 278:2739–2750
pubmed: 21696544
doi: 10.1111/j.1742-4658.2011.08204.x
Ioannou GN (2016) The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol Metab 27:84–95
pubmed: 26703097
doi: 10.1016/j.tem.2015.11.008
Iqbal A, Duitama C, Metge F, Rosskpp D, Boucas J, (2021) Flaski. Zenodo https://doi.org/10.5281/zenodo.4849515
Jhu JW, Yan JB, Lin ZH, Lin SC, Peng IC (2021) SREBP1-induced glutamine synthetase triggers a feedforward loop to upregulate SREBP1 through Sp1 O-GlcNAcylation and augments lipid droplet formation in cancer cells. Int J Mol Sci 22:9814
pubmed: 34575972
pmcid: 8469118
doi: 10.3390/ijms22189814
Kornberg HL (1965) Anaplerotic sequences in microbial metabolism. Angew Chem Int Edit 4:558
doi: 10.1002/anie.196505581
Lee PC, Sever N, Debose-Boyd RA (2005) Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2. J Biol Chem 280:25242–25249
pubmed: 15866869
doi: 10.1074/jbc.M502989200
Liu GY, Sabatini DM (2020) mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 21:183–203
pubmed: 31937935
pmcid: 7102936
doi: 10.1038/s41580-019-0199-y
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Martinez-Reyes I, Chandel NS (2020) Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 11:102
pubmed: 31900386
pmcid: 6941980
doi: 10.1038/s41467-019-13668-3
Maslansky CJ, Williams GM (1982) Primary cultures and the levels of cytochrome P450 in hepatocytes from mouse, rat, hamster, and rabbit liver. In Vitro 18:683–693
pubmed: 7129482
doi: 10.1007/BF02796423
McDonald JG, Thompson BM, McCrum EC, Russell DW (2007) Extraction and analysis of sterols in biological matrices by high performance liquid chromatography electrospray ionization mass spectrometry. Methods Enzymol 432:145–170
pubmed: 17954216
doi: 10.1016/S0076-6879(07)32006-5
Mick E, Titov DV, Skinner OS, Sharma R, Jourdain AA, Mootha VK (2020) Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell. Elife 9:e49178
pubmed: 32463360
pmcid: 7255802
doi: 10.7554/eLife.49178
Motori E, Atanassov I, Kochan SMV, Folz-Donahue K, Sakthivelu V, Giavalisco P, Toni N, Puyal J, Larsson NG (2020) Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction. Sci Adv 6:eaba8271
pubmed: 32923630
pmcid: 7455195
doi: 10.1126/sciadv.aba8271
Mourier A, Motori E, Brandt T, Lagouge M, Atanassov I, Galinier A, Rappl G, Brodesser S, Hultenby K, Dieterich C et al (2015) Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J Cell Biol 208:429–442
pubmed: 25688136
pmcid: 4332246
doi: 10.1083/jcb.201411100
Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2011) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:385–388
pubmed: 22101431
pmcid: 3262117
doi: 10.1038/nature10642
Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ (2000) Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102:315–323
pubmed: 10975522
doi: 10.1016/S0092-8674(00)00037-4
Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277:30409–30412
pubmed: 12087111
doi: 10.1074/jbc.R200006200
Ozbalci C, Sachsenheimer T, Brugger B (2013) Quantitative analysis of cellular lipids by nano-electrospray ionization mass spectrometry. Methods Mol Biol 1033:3–20
pubmed: 23996167
doi: 10.1007/978-1-62703-487-6_1
Pavlova NN, King B, Josselsohn RH, Violante S, Macera VL, Vardhana SA, Cross JR, Thompson CB (2020) Translation in amino-acid-poor environments is limited by tRNA(Gln) charging. Elife 9:e62307
pubmed: 33289483
pmcid: 7744096
doi: 10.7554/eLife.62307
Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, Kramer A, Roncaioli JL, Sand F, Heuckmann JM et al (2015) Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526:700–704
pubmed: 26466568
pmcid: 4881306
doi: 10.1038/nature14980
Pich S, Bach D, Briones P, Liesa M, Camps M, Testar X, Palacin M, Zorzano A (2005) The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 14:1405–1415
pubmed: 15829499
doi: 10.1093/hmg/ddi149
Porter FD, Herman GE (2011) Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res 52:6–34
pubmed: 20929975
pmcid: 2999931
doi: 10.1194/jlr.R009548
Richter U, Lahtinen T, Marttinen P, Myohanen M, Greco D, Cannino G, Jacobs HT, Lietzen N, Nyman TA, Battersby BJ (2013) A mitochondrial ribosomal and RNA decay pathway blocks cell proliferation. Curr Biol 23:535–541
pubmed: 23453957
doi: 10.1016/j.cub.2013.02.019
Robinson MM, McBryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, Hansen JC, Curthoys NP (2007) Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem J 406:407–414
pubmed: 17581113
pmcid: 2049044
doi: 10.1042/BJ20070039
Rocha N, Bulger DA, Frontini A, Titheradge H, Gribsholt SB, Knox R, Page M, Harris J, Payne F, Adams C et al (2017) Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. Elife 6:e23813
pubmed: 28414270
pmcid: 5422073
doi: 10.7554/eLife.23813
Rowe WB, Meister A (1970) Identification of L-methionine-S-sulfoximine as the convulsant isomer of methionine sulfoximine. Proc Natl Acad Sci USA 66:500–506
pubmed: 4393740
pmcid: 283073
doi: 10.1073/pnas.66.2.500
Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL (1996) Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 85:1037–1046
pubmed: 8674110
doi: 10.1016/S0092-8674(00)81304-5
Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC, Goldstein JL, Brown MS (1998) Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 2:505–514
pubmed: 9809072
doi: 10.1016/S1097-2765(00)80150-1
Schumacher MM, DeBose-Boyd RA (2021) Posttranslational regulation of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol. Annu Rev Biochem 90:659–679
pubmed: 34153214
doi: 10.1146/annurev-biochem-081820-101010
Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, Imamichi T, Chang W (2022) DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res 50:W216–221
pubmed: 35325185
pmcid: 9252805
doi: 10.1093/nar/gkac194
Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C et al (2013) Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife 2:e00498
pubmed: 23741617
pmcid: 3667625
doi: 10.7554/eLife.00498
Song Y, Liu J, Zhao K, Gao L, Zhao J (2021) Cholesterol-induced toxicity: an integrated view of the role of cholesterol in multiple diseases. Cell Metab 33:1911–1925
pubmed: 34562355
doi: 10.1016/j.cmet.2021.09.001
Sun LP, Seemann J, Goldstein JL, Brown MS (2007) Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proc Natl Acad Sci USA 104:6519–6526
pubmed: 17428919
pmcid: 1851663
doi: 10.1073/pnas.0700907104
Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, Pimentel H, Salzberg SL, Rinn JL, Pachter L (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7:562–578
pubmed: 22383036
pmcid: 3334321
doi: 10.1038/nprot.2012.016
Wall CTJ, Lefebvre G, Metairon S, Descombes P, Wiederkehr A, Santo-Domingo J (2022) Mitochondrial respiratory chain dysfunction alters ER sterol sensing and mevalonate pathway activity. J Biol Chem 298:101652
pubmed: 35101444
pmcid: 8892029
doi: 10.1016/j.jbc.2022.101652
Wang L, Wang S, Li W (2012) RSeQC: quality control of RNA-seq experiments. Bioinformatics 28:2184–2185
pubmed: 22743226
doi: 10.1093/bioinformatics/bts356
Willis RC, Seegmiller JE (1977) The inhibition by 6-diazo-5-oxo-l-norleucine of glutamine catabolism of the cultured human lymphoblast. J Cell Physiol 93:375–382
pubmed: 22551
doi: 10.1002/jcp.1040930308
Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J, Sudderth J, Calvaruso MA, Lumata L, Mitsche M et al (2014) Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 56:414–424
pubmed: 25458842
pmcid: 4268166
doi: 10.1016/j.molcel.2014.09.025
Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS (2002) 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
pubmed: 12202038
doi: 10.1016/S0092-8674(02)00872-3
Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364
pubmed: 11163209
doi: 10.1016/S1097-2765(00)00133-7
Zelcer N, Sharpe LJ, Loregger A, Kristiana I, Cook EC, 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
pubmed: 24449766
pmcid: 3993563
doi: 10.1128/MCB.01140-13
Zhang J, Liu Q (2015) Cholesterol metabolism and homeostasis in the brain. Protein Cell 6:254–264
pubmed: 25682154
pmcid: 4383754
doi: 10.1007/s13238-014-0131-3
Zhang J, Pavlova NN, Thompson CB (2017) Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J 36:1302–1315
pubmed: 28420743
pmcid: 5430235
doi: 10.15252/embj.201696151
Zhou Y, Eid T, Hassel B, Danbolt NC (2020) Novel aspects of glutamine synthetase in ammonia homeostasis. Neurochem Int 140:104809
pubmed: 32758585
doi: 10.1016/j.neuint.2020.104809