C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases
Autoři:
Yon Ju Ji aff001; Janet Ugolino aff001; Tao Zhang aff001; Jiayin Lu aff001; Dohoon Kim aff001; Jiou Wang aff001
Působiště autorů:
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America
aff001; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America
aff002
Vyšlo v časopise:
C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008738
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008738
Souhrn
Nutrient utilization and energy metabolism are critical for the maintenance of cellular homeostasis. A mutation in the C9orf72 gene has been linked to the most common forms of neurodegenerative diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we have identified an evolutionarily conserved function of C9orf72 in the regulation of the transcription factor EB (TFEB), a master regulator of autophagic and lysosomal genes that is negatively modulated by mTORC1. Loss of the C. elegans orthologue of C9orf72, ALFA-1, causes the nuclear translocation of HLH-30/TFEB, leading to activation of lipolysis and premature lethality during starvation-induced developmental arrest in C. elegans. A similar conserved pathway exists in human cells, in which C9orf72 regulates mTOR and TFEB signaling. C9orf72 interacts with and dynamically regulates the level of Rag GTPases, which are responsible for the recruitment of mTOR and TFEB on the lysosome upon amino acid signals. These results have revealed previously unknown functions of C9orf72 in nutrient sensing and metabolic pathways and suggest that dysregulation of C9orf72 functions could compromise cellular fitness under conditions of nutrient stress.
Klíčová slova:
Autophagic cell death – Caenorhabditis elegans – Co-immunoprecipitation – Guanosine triphosphatase – Lipids – Lysosomes – Phosphorylation – Diapause
Zdroje
1. DeJesus-Hernandez M, Mackenzie Ian R, Boeve Bradley F, Boxer Adam L, Baker M, Rutherford Nicola J, et al. Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron. 2011;72(2):245–56. Epub 2011 Sep 21. doi: 10.1016/j.neuron.2011.09.011 21944778.
2. Renton Alan E, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron. 2011;72(2):257–68. doi: 10.1016/j.neuron.2011.09.010 Epub 2011 Sep 21. 21944779.
3. Van Langenhove T, van der Zee J, Van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Annals of medicine. 2012;44(8):817–28. Epub 2012/03/17. doi: 10.3109/07853890.2012.665471 22420316; PubMed Central PMCID: PMC3529157.
4. Kohli MA, John-Williams K, Rajbhandary R, Naj A, Whitehead P, Hamilton K, et al. Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians. Neurobiology of Aging. 2012. Epub 2012/10/31. doi: 10.1016/j.neurobiolaging.2012.10.003 23107433.
5. Majounie E, Abramzon Y, Renton AE, Perry R, Bassett SS, Pletnikova O, et al. Repeat expansion in C9ORF72 in Alzheimer's disease. N Engl J Med. 2012;366(3):283–4. Epub 2012/01/06. doi: 10.1056/NEJMc1113592 22216764.
6. Rollinson S, Halliwell N, Young K, Callister JB, Toulson G, Gibbons L, et al. Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer's disease. Neurobiology of Aging. 2012;33(8):1846 e5–6. Epub 2012/03/14. doi: 10.1016/j.neurobiolaging.2012.01.109 22410647.
7. Harms M, Benitez BA, Cairns N, Cooper B, Cooper P, Mayo K, et al. C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease. JAMA neurology. 2013;70(6):736–41. Epub 2013/04/17. doi: 10.1001/2013.jamaneurol.537 23588422; PubMed Central PMCID: PMC3681841.
8. Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2014;82(4):292–9. Epub 2013/12/24. doi: 10.1212/WNL.0000000000000061 24363131; PubMed Central PMCID: PMC3929197.
9. Goldman JS, Quinzii C, Dunning-Broadbent J, Waters C, Mitsumoto H, Brannagan TH, 3rd, et al. Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions in C9orf72. JAMA neurology. 2014. Epub 2014/04/16. doi: 10.1001/jamaneurol.2013.5762 24733620.
10. Bieniek KF, van Blitterswijk M, Baker MC, Petrucelli L, Rademakers R, Dickson DW. Expanded C9ORF72 Hexanucleotide Repeat in Depressive Pseudodementia. JAMA neurology. 2014. Epub 2014/04/24. doi: 10.1001/jamaneurol.2013.6368 24756204.
11. Galimberti D, Reif A, Dell'Osso B, Palazzo C, Villa C, Fenoglio C, et al. C9ORF72 hexanucleotide repeat expansion as a rare cause of bipolar disorder. Bipolar disorders. 2014;16(4):448–9. Epub 2013/12/18. doi: 10.1111/bdi.12169 24329881.
12. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012;11(1):54–65. Epub 2011/12/14. doi: 10.1016/S1474-4422(11)70261-7 22154785.
13. Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, Sato C, et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet. 2013;92(6):981–9. Epub 2013/06/05. doi: 10.1016/j.ajhg.2013.04.017 23731538; PubMed Central PMCID: PMC3675239.
14. Belzil VV, Bauer PO, Prudencio M, Gendron TF, Stetler CT, Yan IK, et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol. 2013;126(6):895–905. Epub 2013/10/30. doi: 10.1007/s00401-013-1199-1 24166615; PubMed Central PMCID: PMC3830740.
15. Waite AJ, Baumer D, East S, Neal J, Morris HR, Ansorge O, et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging. 2014;35(7):1779 e5- e13. Epub 2014/02/25. doi: 10.1016/j.neurobiolaging.2014.01.016 24559645; PubMed Central PMCID: PMC3988882.
16. Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG, et al. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol. 2014;128(4):525–41. Epub 2014/05/09. doi: 10.1007/s00401-014-1286-y 24806409; PubMed Central PMCID: PMC4161616.
17. Maharjan N, Kunzli C, Buthey K, Saxena S. C9ORF72 Regulates Stress Granule Formation and Its Deficiency Impairs Stress Granule Assembly, Hypersensitizing Cells to Stress. Mol Neurobiol. 2017;54(4):3062–77. Epub 2016/04/03. doi: 10.1007/s12035-016-9850-1 27037575.
18. Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018. Epub 2018/02/06. doi: 10.1038/nm.4490 29400714.
19. Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014. Epub 2014/02/20. doi: 10.1093/hmg/ddu068 24549040.
20. Sellier C, Campanari ML, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M, et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016. doi: 10.15252/embj.201593350 27103069.
21. O'Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, et al. C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016;351(6279):1324–9. doi: 10.1126/science.aaf1064 26989253.
22. Amick J, Roczniak-Ferguson A, Ferguson SM. C9orf72 binds SMCR8, localizes to lysosomes and regulates mTORC1 signaling. Mol Biol Cell. 2016. doi: 10.1091/mbc.E16-01-0003 27559131.
23. Jung J, Nayak A, Schaeffer V, Starzetz T, Kirsch AK, Muller S, et al. Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator. Elife. 2017;6. doi: 10.7554/eLife.23063 28195531.
24. Sullivan PM, Zhou X, Robins AM, Paushter DH, Kim D, Smolka MB, et al. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun. 2016;4(1):51. doi: 10.1186/s40478-016-0324-5 27193190; PubMed Central PMCID: PMC4870812.
25. Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L, et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 2016;35(15):1656–76. doi: 10.15252/embj.201694401 27334615.
26. Yang M, Liang C, Swaminathan K, Herrlinger S, Lai F, Shiekhattar R, et al. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. 2016;2(9):e1601167. doi: 10.1126/sciadv.1601167 27617292; PubMed Central PMCID: PMC5010369.
27. Ugolino J, Ji YJ, Conchina K, Chu J, Nirujogi RS, Pandey A, et al. Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling. PLoS Genet. 2016;12(11):e1006443. doi: 10.1371/journal.pgen.1006443 27875531; PubMed Central PMCID: PMC5119725.
28. Aoki Y, Manzano R, Lee Y, Dafinca R, Aoki M, Douglas AGL, et al. C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia. Brain. 2017;140(4):887–97. Epub 2017/03/24. doi: 10.1093/brain/awx024 28334866.
29. Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, Stewart MH, et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Science translational medicine. 2016;8(347):347ra93. doi: 10.1126/scitranslmed.aaf6038 27412785.
30. Liu Y, Wang T, Ji YJ, Johnson K, Liu H, Johnson K, et al. A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress. Genes Dev. 2018;32(21–22):1380–97. Epub 2018/10/28. doi: 10.1101/gad.315564.118 30366907; PubMed Central PMCID: PMC6217731.
31. Therrien M, Rouleau GA, Dion PA, Parker JA. Deletion of C9ORF72 Results in Motor Neuron Degeneration and Stress Sensitivity in C. elegans. PLoS One. 2013;8(12):e83450. Epub 2013/12/19. doi: 10.1371/journal.pone.0083450 24349511; PubMed Central PMCID: PMC3861484.
32. Corrionero A, Horvitz HR. A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis. Curr Biol. 2018;28(10):1522–35 e5. Epub 2018/05/08. doi: 10.1016/j.cub.2018.03.063 29731301.
33. Baugh LR, Sternberg PW. DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest. Curr Biol. 2006;16(8):780–5. Epub 2006/04/25. doi: 10.1016/j.cub.2006.03.021 16631585.
34. Kaplan RE, Chen Y, Moore BT, Jordan JM, Maxwell CS, Schindler AJ, et al. dbl-1/TGF-beta and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest. PLoS Genet. 2015;11(12):e1005731. Epub 2015/12/15. doi: 10.1371/journal.pgen.1005731 26656736; PubMed Central PMCID: PMC4676721.
35. Harvald EB, Sprenger RR, Dall KB, Ejsing CS, Nielsen R, Mandrup S, et al. Multi-omics Analyses of Starvation Responses Reveal a Central Role for Lipoprotein Metabolism in Acute Starvation Survival in C. elegans. Cell Syst. 2017;5(1):38–52 e4. Epub 2017/07/25. doi: 10.1016/j.cels.2017.06.004 28734827.
36. Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature. 2003;421(6920):268–72. Epub 2003/01/17. doi: 10.1038/nature01279 12529643.
37. O'Rourke EJ, Soukas AA, Carr CE, Ruvkun G. C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell metabolism. 2009;10(5):430–5. Epub 2009/11/04. doi: 10.1016/j.cmet.2009.10.002 19883620; PubMed Central PMCID: PMC2921818.
38. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325(5939):473–7. doi: 10.1126/science.1174447 19556463.
39. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332(6036):1429–33. doi: 10.1126/science.1204592 21617040; PubMed Central PMCID: PMC3638014.
40. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol. 2013;15(6):647–58. Epub 2013/04/23. doi: 10.1038/ncb2718 23604321; PubMed Central PMCID: PMC3699877.
41. O'Rourke EJ, Ruvkun G. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat Cell Biol. 2013;15(6):668–76. Epub 2013/04/23. doi: 10.1038/ncb2741 23604316; PubMed Central PMCID: PMC3723461.
42. Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT, et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nature communications. 2013;4:2267. doi: 10.1038/ncomms3267 23925298; PubMed Central PMCID: PMC3866206.
43. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Science signaling. 2012;5(228):ra42. Epub 2012/06/14. doi: 10.1126/scisignal.2002790 22692423; PubMed Central PMCID: PMC3437338.
44. Kang C, You YJ, Avery L. Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation. Genes Dev. 2007;21(17):2161–71. Epub 2007/09/06. doi: 10.1101/gad.1573107 17785524; PubMed Central PMCID: PMC1950855.
45. Meléndez A, Tallóczy Z, Seaman M, Eskelinen E-L, Hall DH, Levine B. Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans. Science. 2003;301(5638):1387–91. doi: 10.1126/science.1087782 12958363
46. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8(6):903–14. Epub 2012/05/12. doi: 10.4161/auto.19653 22576015; PubMed Central PMCID: PMC3427256.
47. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31(5):1095–108. Epub 2012/02/22. doi: 10.1038/emboj.2012.32 22343943; PubMed Central PMCID: PMC3298007.
48. Martina JA, Puertollano R. Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol. 2013;200(4):475–91. Epub 2013/02/13. doi: 10.1083/jcb.201209135 23401004; PubMed Central PMCID: PMC3575543.
49. Schurmann A, Brauers A, Massmann S, Becker W, Joost HG. Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J Biol Chem. 1995;270(48):28982–8. Epub 1995/12/01. doi: 10.1074/jbc.270.48.28982 7499430.
50. Sekiguchi T, Hirose E, Nakashima N, Ii M, Nishimoto T. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem. 2001;276(10):7246–57. Epub 2000/11/14. doi: 10.1074/jbc.M004389200 11073942.
51. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008;10(8):935–45. Epub 2008/07/08. doi: 10.1038/ncb1753 18604198; PubMed Central PMCID: PMC2711503.
52. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320(5882):1496–501. Epub 2008/05/24. doi: 10.1126/science.1157535 18497260; PubMed Central PMCID: PMC2475333.
53. Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52(4):495–505. Epub 2013/10/08. doi: 10.1016/j.molcel.2013.09.016 24095279; PubMed Central PMCID: PMC3867817.
54. Goberdhan DC, Wilson C, Harris AL. Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot. Cell metabolism. 2016;23(4):580–9. Epub 2016/04/15. doi: 10.1016/j.cmet.2016.03.013 27076075; PubMed Central PMCID: PMC5067300.
55. Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A, et al. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol. 2013;74(2):180–7. Epub 2013/05/31. doi: 10.1002/ana.23946 23720273.
56. Shao Q, Liang C, Chang Q, Zhang W, Yang M, Chen JF. C9orf72 deficiency promotes motor deficits of a C9ALS/FTD mouse model in a dose-dependent manner. Acta Neuropathol Commun. 2019;7(1):32. Epub 2019/03/06. doi: 10.1186/s40478-019-0685-7 30832726.
57. Wang M, Wang H, Tao Z, Xia Q, Hao Z, Prehn JHM, et al. C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis. Aging Cell. 2020:e13126. Epub 2020/02/27. doi: 10.1111/acel.13126 32100453.
58. Yamamoto A, Yue Z. Autophagy and its normal and pathogenic states in the brain. Annu Rev Neurosci. 2014;37:55–78. Epub 2014/05/14. doi: 10.1146/annurev-neuro-071013-014149 24821313.
59. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983–97. Epub 2013/08/08. doi: 10.1038/nm.3232 23921753.
60. Kao AW, McKay A, Singh PP, Brunet A, Huang EJ. Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci. 2017;18(6):325–33. Epub 2017/04/25. doi: 10.1038/nrn.2017.36 28435163; PubMed Central PMCID: PMC6040832.
61. Nguyen DKH, Thombre R, Wang J. Autophagy as a common pathway in amyotrophic lateral sclerosis. Neurosci Lett. 2018. Epub 2018/04/08. doi: 10.1016/j.neulet.2018.04.006 29626651.
62. Zhang T, Hwang HY, Hao H, Talbot C Jr., Wang J. Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span. The Journal of biological chemistry. 2012;287(11):8371–82. Epub 2012/01/11. doi: 10.1074/jbc.M111.311977 22232551; PubMed Central PMCID: PMC3318719.
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