Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis

English version České info

Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (tti^s450), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In tti^s450, the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in tti^s450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in tti^s450 larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death.

Vyšlo v časopise: Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003279
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003279

Souhrn

Zdroje

1. WarnerJR (2001) Nascent ribosomes. Cell 107 : 133–136.

2. DoudnaJA, RathVL (2002) Structure and function of the eukaryotic ribosome: the next frontier. Cell 109 : 153–156.

3. JorgensenP, TyersM (2004) How cells coordinate growth and division. Curr Biol 14: R1014–1027.

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

5. StumpfCR, RuggeroD (2011) The cancerous translation apparatus. Curr Opin Genet Dev 21 : 474–483.

6. Fromont-RacineM, SengerB, SaveanuC, FasioloF (2003) Ribosome assembly in eukaryotes. Gene 313 : 17–42.

7. GrandiP, RybinV, BasslerJ, PetfalskiE, StraussD, et al. (2002) 90S pre-ribosomes include the 35S pre-rRNA, the U3 snoRNP, and 40S subunit processing factors but predominantly lack 60S synthesis factors. Mol Cell 10 : 105–115.

8. FerrariS, BandiHR, HofsteengeJ, BussianBM, ThomasG (1991) Mitogen-activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites. J Biol Chem 266 : 22770–22775.

9. GingrasAC, RaughtB, SonenbergN (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68 : 913–963.

10. LevineB, KlionskyDJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6 : 463–477.

11. KraftC, DeplazesA, SohrmannM, PeterM (2008) Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nat Cell Biol 10 : 602–610.

12. KlionskyDJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8 : 931–937.

13. LevineB, KroemerG (2008) Autophagy in the pathogenesis of disease. Cell 132 : 27–42.

14. HeC, KlionskyDJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43 : 67–93.

15. HeC, BassikMC, MoresiV, SunK, WeiY, et al. (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481 : 511–515.

16. FengZ, HuW, de StanchinaE, TereskyAK, JinS, et al. (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 67 : 3043–3053.

17. HosokawaN, HaraT, KaizukaT, KishiC, TakamuraA, et al. (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20 : 1981–1991.

18. HosokawaN, SasakiT, IemuraS, NatsumeT, HaraT, et al. (2009) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5 : 973–979.

19. LeeJW, ParkS, TakahashiY, WangHG (2010) The association of AMPK with ULK1 regulates autophagy. PLoS ONE 5: e15394 doi:10.1371/journal.pone.0015394.

20. EganDF, ShackelfordDB, MihaylovaMM, GelinoS, KohnzRA, et al. (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331 : 456–461.

21. KimJ, KunduM, ViolletB, GuanKL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13 : 132–141.

22. RoachPJ (2011) AMPK→ULK1→autophagy. Mol Cell Biol 31 : 3082–3084.

23. OberEA, VerkadeH, FieldHA, StainierDY (2006) Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442 : 688–691.

24. DosilM, BusteloXR (2004) Functional characterization of Pwp2, a WD family protein essential for the assembly of the 90 S pre-ribosomal particle. J Biol Chem 279 : 37385–37397.

25. BernsteinKA, BleichertF, BeanJM, CrossFR, BasergaSJ (2007) Ribosome biogenesis is sensed at the Start cell cycle checkpoint. Mol Biol Cell 18 : 953–964.

26. FieldHA, OberEA, RoeserT, StainierDY (2003) Formation of the digestive system in zebrafish. I. Liver morphogenesis. Dev Biol 253 : 279–290.

27. NgAN, de Jong-CurtainTA, MawdsleyDJ, WhiteSJ, ShinJ, et al. (2005) Formation of the digestive system in zebrafish: III. Intestinal epithelium morphogenesis. Dev Biol 286 : 114–135.

28. de Jong-CurtainTA, ParslowAC, TrotterAJ, HallNE, VerkadeH, et al. (2009) Abnormal nuclear pore formation triggers apoptosis in the intestinal epithelium of elys-deficient zebrafish. Gastroenterology 136 : 902–911.

29. DavuluriG, GongW, YusuffS, LorentK, MuthumaniM, et al. (2008) Mutation of the zebrafish nucleoporin elys sensitizes tissue progenitors to replication stress. PLoS Genet 4: e1000240 doi:10.1371/journal.pgen.1000240.

30. AndersonRM, BoschJA, GollMG, HesselsonD, DongPD, et al. (2009) Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration. Dev Biol 334 : 213–223.

31. FarooqM, SulochanaKN, PanX, ToJ, ShengD, et al. (2008) Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish. Dev Biol 317 : 336–353.

32. BoulonS, WestmanBJ, HuttenS, BoisvertFM, LamondAI (2010) The nucleolus under stress. Mol Cell 40 : 216–227.

33. CuiJ, SimTH, GongZ, ShenHM (2012) Generation of transgenic zebrafish with liver-specific expression of EGFP-Lc3: a new in vivo model for investigation of liver autophagy. Biochem Biophys Res Commun 422 : 268–273.

34. HeC, BartholomewCR, ZhouW, KlionskyDJ (2009) Assaying autophagic activity in transgenic GFP-Lc3 and GFP-Gabarap zebrafish embryos. Autophagy 5 : 520–526.

35. NodaT, OhsumiY (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273 : 3963–3966.

36. HuZ, ZhangJ, ZhangQ (2011) Expression pattern and functions of autophagy-related gene atg5 in zebrafish organogenesis. Autophagy 7 : 1514–1527.

37. MarshallKE, TomasiniAJ, MakkyK, KumarS, MayerAN (2010) Dynamic lkb1-TORC1 signaling as a possible mechanism for regulating the endoderm-intestine transition. Dev Dyn

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

39. ZengX, KinsellaTJ (2008) Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res 68 : 2384–2390.

40. KimSH, SpeirsCK, Solnica-KrezelL, EssKC (2011) Zebrafish model of tuberous sclerosis complex reveals cell-autonomous and non-cell-autonomous functions of mutant tuberin. Dis Model Mech 4 : 255–267.

41. ZhangY, LuH (2009) Signaling to p53: ribosomal proteins find their way. Cancer Cell 16 : 369–377.

42. MaiuriMC, GalluzziL, MorselliE, KeppO, MalikSA, et al. (2010) Autophagy regulation by p53. Curr Opin Cell Biol 22 : 181–185.

43. 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.

44. LeeversSJ, McNeillH (2005) Controlling the size of organs and organisms. Curr Opin Cell Biol 17 : 604–609.

45. MayerAN, FishmanMC (2003) Nil per os encodes a conserved RNA recognition motif protein required for morphogenesis and cytodifferentiation of digestive organs in zebrafish. Development 130 : 3917–3928.

46. MakkyK, TekielaJ, MayerAN (2007) Target of rapamycin (TOR) signaling controls epithelial morphogenesis in the vertebrate intestine. Dev Biol 303 : 501–513.

47. AlersS, LofflerAS, WesselborgS, StorkB (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32 : 2–11.

48. BehrendsC, SowaME, GygiSP, HarperJW (2010) Network organization of the human autophagy system. Nature 466 : 68–76.

49. BudovskayaYV, StephanJS, ReggioriF, KlionskyDJ, HermanPK (2004) The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. J Biol Chem 279 : 20663–20671.

50. YorimitsuT, ZamanS, BroachJR, KlionskyDJ (2007) Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 18 : 4180–4189.

51. XuP, DasM, ReillyJ, DavisRJ (2011) JNK regulates FoxO-dependent autophagy in neurons. Genes Dev 25 : 310–322.

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

53. KimI, Rodriguez-EnriquezS, LemastersJJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462 : 245–253.

54. KroemerG, LevineB (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9 : 1004–1010.

55. 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.

56. ZhangY, MorimotoK, DanilovaN, ZhangB, LinS (2012) Zebrafish Models for Dyskeratosis Congenita Reveal Critical Roles of p53 Activation Contributing to Hematopoietic Defects through RNA Processing. PLoS ONE 7: e30188 doi:10.1371/journal.pone.0030188.

57. ReichenbachB, DelalandeJM, KolmogorovaE, PrierA, NguyenT, et al. (2008) Endoderm-derived Sonic hedgehog and mesoderm Hand2 expression are required for enteric nervous system development in zebrafish. Dev Biol 318 : 52–64.

58. ChristieEL, ParslowAC, HeathJK (2008) Determination of mRNA and protein expression patterns in zebrafish. Methods Mol Biol 469 : 253–272.

59. ChomczynskiP, SacchiN (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162 : 156–159.

60. AzumaM, ToyamaR, LaverE, DawidIB (2006) Perturbation of rRNA synthesis in the bap28 mutation leads to apoptosis mediated by p53 in the zebrafish central nervous system. J Biol Chem 281 : 13309–13316.

61. ChanJC, HannanKM, RiddellK, NgPY, PeckA, et al. (2011) AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. Sci Signal 4: ra56.

62. SpurrAR (1969) A low-viscosity epoxy resin embedding medium for electron microscopy. J Ultrastruct Res 26 : 31–43.