Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

English version České info

Diseases linked to mutations affecting the ribosome, ribosomopathies, have an exceptionally wide range of phenotypes. However, many ribosomopathies have some features in common including cytopenia and growth defects. Our study aims to clarify the mechanisms behind these common phenotypes. We find that mutations in ribosomal protein genes result in a series of aberrant signaling events that cause cells to start recycling and consuming their own intracellular contents. This basic mechanism of catabolism is activated when cells are starving for nutrients, and also during the tightly regulated process of blood cell maturation. The deregulation of this mechanism provides an explanation as to why blood cells are so acutely affected by mutations in genes that impair the ribosome. Moreover, we find that the signals activating this catabolism are coupled to impairment of the highly conserved insulin-signaling pathway that is essential for growth. Taken together, our in-depth description of the pathways involved as the result of mutations affecting the ribosome increases our understanding about the etiology of these diseases and opens up previously unknown avenues of potential treatment.

Vyšlo v časopise: Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004371
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004371

Souhrn

Zdroje

1. NarlaA, EbertBL (2010) Ribosomopathies: human disorders of ribosome dysfunction. Blood 115: 3196–3205.

2. EbertBL, PretzJ, BoscoJ, ChangCY, TamayoP, et al. (2008) Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451: 335–339.

3. BoriaI, GarelliE, GazdaHT, AspesiA, QuarelloP, et al. (2010) The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. Human mutation 31: 1269–1279.

4. LiptonJM, KudischM, GrossR, NathanDG (1986) Defective erythroid progenitor differentiation system in congenital hypoplastic (Diamond-Blackfan) anemia. Blood 67: 962–968.

5. Ohene-AbuakwaY, OrfaliKA, MariusC, BallSE (2005) Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect. Blood 105: 838–846.

6. OliverER, SaundersTL, TarleSA, GlaserT (2004) Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131: 3907–3920.

7. LaiK, AmsterdamA, FarringtonS, BronsonRT, HopkinsN, et al. (2009) Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish. Dev Dyn 238: 76–85.

8. VlachosA, BallS, DahlN, AlterBP, ShethS, et al. (2008) Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol 142: 859–876.

9. SmithOP (2002) Shwachman-Diamond syndrome. Semin Hematol 39: 95–102.

10. YaghmaiR, Kimyai-AsadiA, RostamianiK, HeissNS, PoustkaA, et al. (2000) Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome. J Pediatr 136: 390–393.

11. DuttS, NarlaA, LinK, MullallyA, AbayasekaraN, et al. (2011) Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 117: 2567–2576.

12. ChenY, KlionskyDJ (2011) The regulation of autophagy - unanswered questions. Journal of cell science 124: 161–170.

13. KunduM, ThompsonCB (2008) Autophagy: basic principles and relevance to disease. Annu Rev Pathol 3: 427–455.

14. ShintaniT, KlionskyDJ (2004) Autophagy in health and disease: a double-edged sword. Science 306: 990–995.

15. MortensenM, SoilleuxEJ, DjordjevicG, TrippR, LutteroppM, et al. (2011) The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med 208: 455–467.

16. SandovalH, ThiagarajanP, DasguptaSK, SchumacherA, PrchalJT, et al. (2008) Essential role for Nix in autophagic maturation of erythroid cells. Nature 454: 232–235.

17. PowersT, WalterP (1999) Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 10: 987–1000.

18. MartinDE, SoulardA, HallMN (2004) TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL1. Cell 119: 969–979.

19. KamadaY, FunakoshiT, ShintaniT, NaganoK, OhsumiM, et al. (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150: 1507–1513.

20. MagnusonB, EkimB, FingarDC (2012) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 441: 1–21.

21. ShahbazianD, RouxPP, MieuletV, CohenMS, RaughtB, et al. (2006) The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. The EMBO journal 25: 2781–2791.

22. WangX, LiW, WilliamsM, TeradaN, AlessiDR, et al. (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. The EMBO journal 20: 4370–4379.

23. ScottRC, SchuldinerO, NeufeldTP (2004) Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 7: 167–178.

24. HayN, SonenbergN (2004) Upstream and downstream of mTOR. Genes Dev 18: 1926–1945.

25. BarthelA, OkinoST, LiaoJ, NakataniK, LiJ, et al. (1999) Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 274: 20281–20286.

26. CongLN, ChenH, LiY, ZhouL, McGibbonMA, et al. (1997) Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol Endocrinol 11: 1881–1890.

27. ShahOJ, WangZ, HunterT (2004) Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14: 1650–1656.

28. UmSH, D'AlessioD, ThomasG (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3: 393–402.

29. MelendezA, TalloczyZ, SeamanM, EskelinenEL, HallDH, et al. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301: 1387–1391.

30. SeglenPO, BohleyP (1992) Autophagy and other vacuolar protein degradation mechanisms. Experientia 48: 158–172.

31. WangRC, WeiY, AnZ, ZouZ, XiaoG, et al. (2012) Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338: 956–959.

32. KangR, ZehHJ, LotzeMT, TangD (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18: 571–580.

33. KlionskyDJ, CuervoAM, SeglenPO (2007) Methods for monitoring autophagy from yeast to human. Autophagy 3: 181–206.

34. YamamotoA, TagawaY, YoshimoriT, MoriyamaY, MasakiR, et al. (1998) Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 23: 33–42.

35. BellodiC, LidonniciMR, HamiltonA, HelgasonGV, SolieraAR, et al. (2009) Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest 119: 1109–1123.

36. IchimuraY, KomatsuM (2010) Selective degradation of p62 by autophagy. Semin Immunopathol 32: 431–436.

37. AmsterdamA, SadlerKC, LaiK, FarringtonS, BronsonRT, et al. (2004) Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol 2: E139.

38. DanilovaN, SakamotoKM, LinS (2008) Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood 112: 5228–5237.

39. JaakoP, FlygareJ, OlssonK, QuereR, EhingerM, et al. (2011) Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia. Blood 118: 6087–6096.

40. DanilovaN, SakamotoKM, LinS (2011) Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects. British journal of haematology 152: 217–228.

41. HaileyDW, RamboldAS, Satpute-KrishnanP, MitraK, SougratR, et al. (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141: 656–667.

42. DingWX, LiM, BiazikJM, MorganDG, GuoF, et al. (2012) Electron microscopic analysis of a spherical mitochondrial structure. The Journal of biological chemistry 287: 42373–42378.

43. PayneEM, VirgilioM, NarlaA, SunH, LevineM, et al. (2012) L-Leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway. Blood 120: 2214–2224.

44. PedersonTM, KramerDL, RondinoneCM (2001) Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 50: 24–31.

45. LiM, ZhaoL, LiuJ, LiuA, JiaC, et al. (2010) Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling. Cell Signal 22: 1469–1476.

46. HamadI, ArdaN, PekmezM, KaraerS, TemizkanG (2010) Intracellular scavenging activity of Trolox (6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid) in the fission yeast, Schizosaccharomyces pombe. J Nat Sci Biol Med 1: 16–21.

47. KumarS, KumarA, PathaniaAS, GuruSK, JadaS, et al. (2013) Tiron and trolox potentiate the autophagic cell death induced by magnolol analog Ery5 by activation of Bax in HL-60 cells. Apoptosis 18: 605–617.

48. AmsterdamA, BurgessS, GollingG, ChenW, SunZ, et al. (1999) A large-scale insertional mutagenesis screen in zebrafish. Genes Dev 13: 2713–2724.

49. LiuB, ChenY, St ClairDK (2008) ROS and p53: a versatile partnership. Free Radic Biol Med 44: 1529–1535.

50. BerghmansS, MurpheyRD, WienholdsE, NeubergD, KutokJL, et al. (2005) tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A 102: 407–412.

51. GuoL, LiewHP, CamusS, GohAM, CheeLL, et al. (2013) Ionizing radiation induces a dramatic persistence of p53 protein accumulation and DNA damage signaling in mutant p53 zebrafish. Oncogene 32: 4009–4016.

52. FinchAJ, HilcenkoC, BasseN, DrynanLF, GoyenecheaB, et al. (2011) Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev 25: 917–929.

53. WoloszynekJR, RothbaumRJ, RawlsAS, MinxPJ, WilsonRK, et al. (2004) Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome. Blood 104: 3588–3590.

54. HartlTA, NiJ, CaoJ, SuyamaKL, PatchettS, et al. (2013) Regulation of ribosome biogenesis by nucleostemin 3 promotes local and systemic growth in Drosophila. Genetics 194: 101–115.

55. BoglevY, BadrockAP, TrotterAJ, DuQ, RichardsonEJ, et al. (2013) Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis. PLoS Genet 9: e1003279.

56. PayneE, VirgilioM, NarlaA, SunH, LevineM, et al. (2012) L-Leucine improves anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q)MDS by activating the mTOR pathway. Blood 120: 2214–2224.

57. FinkelT (2011) Signal transduction by reactive oxygen species. J Cell Biol 194: 7–15.

58. PereboevaL, WestinE, PatelT, FlanikenI, LambL, et al. (2013) DNA damage responses and oxidative stress in dyskeratosis congenita. PLoS ONE 8: e76473.

59. KumariU, Ya JunW, Huat BayB, LyakhovichA (2014) Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi Anemia cells. Oncogene 33: 165–172.

60. AmbekarC, DasB, YegerH, DrorY (2010) SBDS-deficiency results in deregulation of reactive oxygen species leading to increased cell death and decreased cell growth. Pediatr Blood Cancer 55: 1138–1144.

61. CeccaldiR, ParmarK, MoulyE, DelordM, KimJM, et al. (2012) Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell 11: 36–49.

62. MiyagawaS, KobayashiM, KonishiN, SatoT, UedaK (2000) Insulin and insulin-like growth factor I support the proliferation of erythroid progenitor cells in bone marrow through the sharing of receptors. Br J Haematol 109: 555–562.

63. ZhangH, LiuJ, LiCR, MomenB, KohanskiRA, et al. (2009) Deletion of Drosophila insulin-like peptides causes growth defects and metabolic abnormalities. Proc Natl Acad Sci U S A 106: 19617–19622.

64. DuvillieB, CordonnierN, DeltourL, Dandoy-DronF, ItierJM, et al. (1997) Phenotypic alterations in insulin-deficient mutant mice. Proc Natl Acad Sci U S A 94: 5137–5140.

65. UnderwoodBR, ImarisioS, FlemingA, RoseC, KrishnaG, et al. (2010) Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet 19: 3413–3429.

66. MacInnesAW, AmsterdamA, WhittakerCA, HopkinsN, LeesJA (2008) Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations. Proc Natl Acad Sci U S A 105: 10408–10413.

67. MonizH, GastouM, LeblancT, HurtaudC, CretienA, et al. (2012) Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro. Cell Death Dis 3: e356.

68. PereboomTC, van WeeleLJ, BondtA, MacInnesAW (2011) A zebrafish model of dyskeratosis congenita reveals hematopoietic stem cell formation failure resulting from ribosomal protein-mediated p53 stabilization. Blood 118: 5458–5465.