Translational Regulation of the DOUBLETIME/CKIδ/ε Kinase by LARK Contributes to Circadian Period Modulation

English version České info

The CKI family of serine/threonine kinase regulates diverse cellular processes, through binding to and phosphorylation of a variety of protein substrates. In mammals, mutations in two members of the family, CKIε and CKIδ were found to affect circadian period length, causing phenotypes such as altered circadian period in rodents and the Familial Advanced Sleep Phase Syndrome (FASPS) in human. The Drosophila CKI δ/ε homolog DOUBLETIME (DBT) is known to have important roles in development and circadian clock function. Despite extensive studies of DBT function, little is known about how its expression is regulated. In a previous genome-wide study, we identified dbt mRNAs as potential targets of the LARK RBP. Here we describe a detailed study of the regulation of DBT expression by LARK. We found that LARK binds to and regulates translation of dbt mRNA, promoting expression of a smaller isoform; we suggest this regulatory mechanism contributes to circadian period determination. In addition, we have identified a dbt mRNA that exhibits light-induced changes in translational status, in a LARK-dependent manner. Our study is the first to analyze the translational regulation of DBT, setting the stage for similar studies in other contexts and model systems.

Vyšlo v časopise: Translational Regulation of the DOUBLETIME/CKIδ/ε Kinase by LARK Contributes to Circadian Period Modulation. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004536
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004536

Souhrn

Zdroje

1. KlossB, PriceJL, SaezL, BlauJ, RothenfluhA, et al. (1998) The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94: 97–107.

2. PriceJL, BlauJ, RothenfluhA, AbodeelyM, KlossB, et al. (1998) double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94: 83–95.

3. ZilianO, FreiE, BurkeR, BrentrupD, GutjahrT, et al. (1999) double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs. Development 126: 5409–5420.

4. KleinTJ, JennyA, DjianeA, MlodzikM (2006) CKIepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in Drosophila. Curr Biol 16: 1337–1343.

5. ZhangL, JiaJ, WangB, AmanaiK, WhartonKAJr, et al. (2006) Regulation of wingless signaling by the CKI family in Drosophila limb development. Dev Biol 299: 221–237.

6. PriceMA, KalderonD (2002) Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 108: 823–835.

7. JiaJ, TongC, WangB, LuoL, JiangJ (2004) Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432: 1045–1050.

8. JiaJ, ZhangL, ZhangQ, TongC, WangB, et al. (2005) Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. Dev Cell 9: 819–830.

9. SuY, OspinaJK, ZhangJ, MichelsonAP, SchoenAM, et al. (2011) Sequential phosphorylation of smoothened transduces graded hedgehog signaling. Sci Signal 4: ra43.

10. ChoE, FengY, RauskolbC, MaitraS, FehonR, et al. (2006) Delineation of a Fat tumor suppressor pathway. Nat Genet 38: 1142–1150.

11. FengY, IrvineKD (2009) Processing and phosphorylation of the Fat receptor. Proc Natl Acad Sci U S A 106: 11989–11994.

12. SopkoR, SilvaE, ClaytonL, GardanoL, Barrios-RodilesM, et al. (2009) Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown. Curr Biol 19: 1112–1117.

13. PanG, FengY, AmbegaonkarAA, SunG, HuffM, et al. (2013) Signal transduction by the Fat cytoplasmic domain. Development 140: 831–842.

14. MiltonCC, ZhangX, AlbaneseNO, HarveyKF (2010) Differential requirement of Salvador-Warts-Hippo pathway members for organ size control in Drosophila melanogaster. Development 137: 735–743.

15. RauskolbC, PanG, ReddyBV, OhH, IrvineKD (2011) Zyxin links fat signaling to the hippo pathway. PLoS Biol 9: e1000624.

16. EideEJ, VirshupDM (2001) Casein kinase I: another cog in the circadian clockworks. Chronobiol Int 18: 389–398.

17. OzkayaO, RosatoE (2012) The circadian clock of the fly: a neurogenetics journey through time. Adv Genet 77: 79–123.

18. HardinPE (2011) Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74: 141–173.

19. Lakin-ThomasPL, Bell-PedersenD, BrodyS (2011) The genetics of circadian rhythms in Neurospora. Adv Genet 74: 55–103.

20. MackeySR, GoldenSS, DittyJL (2011) The itty-bitty time machine genetics of the cyanobacterial circadian clock. Adv Genet 74: 13–53.

21. McClungCR (2011) The genetics of plant clocks. Adv Genet 74: 105–139.

22. LowreyPL, TakahashiJS (2011) Genetics of circadian rhythms in Mammalian model organisms. Adv Genet 74: 175–230.

23. van OoijenG, MillarAJ (2012) Non-transcriptional oscillators in circadian timekeeping. Trends Biochem Sci 37: 484–492.

24. LowreyPL, ShimomuraK, AntochMP, YamazakiS, ZemenidesPD, et al. (2000) Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288: 483–492.

25. LoudonAS, MengQJ, MaywoodES, BechtoldDA, Boot-HandfordRP, et al. (2007) The biology of the circadian Ck1epsilon tau mutation in mice and Syrian hamsters: a tale of two species. Cold Spring Harb Symp Quant Biol 72: 261–271.

26. Smadja StorzS, TovinA, MracekP, AlonS, FoulkesNS, et al. (2013) Casein kinase 1delta activity: a key element in the zebrafish circadian timing system. PLoS One 8: e54189.

27. JonesCR, CampbellSS, ZoneSE, CooperF, DeSanoA, et al. (1999) Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nat Med 5: 1062–1065.

28. TohKL, JonesCR, HeY, EideEJ, HinzWA, et al. (2001) An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291: 1040–1043.

29. XuY, TohKL, JonesCR, ShinJY, FuYH, et al. (2007) Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 128: 59–70.

30. VanselowK, VanselowJT, WestermarkPO, ReischlS, MaierB, et al. (2006) Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev 20: 2660–2672.

31. ShanwareNP, HutchinsonJA, KimSH, ZhanL, BowlerMJ, et al. (2011) Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem 286: 12766–12774.

32. XuY, PadiathQS, ShapiroRE, JonesCR, WuSC, et al. (2005) Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434: 640–644.

33. KlossB, RothenfluhA, YoungMW, SaezL (2001) Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless in the Drosophila clock. Neuron 30: 699–706.

34. KoHW, JiangJ, EderyI (2002) Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature 420: 673–678.

35. GrimaB, LamourouxA, ChelotE, PapinC, Limbourg-BouchonB, et al. (2002) The F-box protein slimb controls the levels of clock proteins period and timeless. Nature 420: 178–182.

36. KimEY, KoHW, YuW, HardinPE, EderyI (2007) A DOUBLETIME kinase binding domain on the Drosophila PERIOD protein is essential for its hyperphosphorylation, transcriptional repression, and circadian clock function. Mol Cell Biol 27: 5014–5028.

37. NawatheanP, StoleruD, RosbashM (2007) A small conserved domain of Drosophila PERIOD is important for circadian phosphorylation, nuclear localization, and transcriptional repressor activity. Mol Cell Biol 27: 5002–5013.

38. KivimaeS, SaezL, YoungMW (2008) Activating PER repressor through a DBT-directed phosphorylation switch. PLoS Biol 6: e183.

39. ChiuJC, KoHW, EderyI (2011) NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell 145: 357–370.

40. ChiuJC, VanselowJT, KramerA, EderyI (2008) The phospho-occupancy of an atypical SLIMB-binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock. Genes Dev 22: 1758–1772.

41. KimEY, EderyI (2006) Balance between DBT/CKIepsilon kinase and protein phosphatase activities regulate phosphorylation and stability of Drosophila CLOCK protein. Proc Natl Acad Sci U S A 103: 6178–6183.

42. YuW, ZhengH, HoulJH, DauwalderB, HardinPE (2006) PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription. Genes Dev 20: 723–733.

43. YuW, ZhengH, PriceJL, HardinPE (2009) DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock. Mol Cell Biol 29: 1452–1458.

44. HuangY, GenovaG, RobertsM, JacksonFR (2007) The LARK RNA-binding protein selectively regulates the circadian eclosion rhythm by controlling E74 protein expression. PLoS ONE 2: e1107.

45. NewbyLM, JacksonFR (1993) A new biological rhythm mutant of Drosophila melanogaster that identifies a gene with an essential embryonic function. Genetics 135: 1077–1090.

46. NewbyLM, JacksonFR (1996) Regulation of a specific circadian clock output pathway by lark, a putative RNA-binding protein with repressor activity. J Neurobiol 31: 117–128.

47. McNeilGP, ZhangX, GenovaG, JacksonFR (1998) A molecular rhythm mediating circadian clock output in Drosophila. Neuron 20: 297–303.

48. McNeilGP, SchroederAJ, RobertsMA, JacksonFR (2001) Genetic analysis of functional domains within the Drosophila LARK RNA-binding protein. Genetics 159: 229–240.

49. SchroederAJ, GenovaGK, RobertsMA, KleynerY, SuhJ, et al. (2003) Cell-specific expression of the lark RNA-binding protein in Drosophila results in morphological and circadian behavioral phenotypes. J Neurogenet 17: 139–169.

50. HuangY, HowlettE, SternM, JacksonFR (2009) Altered LARK expression perturbs development and physiology of the Drosophila PDF clock neurons. Mol Cell Neurosci 41: 196–205.

51. SundramV, NgFS, RobertsMA, MillanC, EwerJ, et al. (2012) Cellular requirements for LARK in the Drosophila circadian system. J Biol Rhythms 27: 183–195.

52. KojimaS, MatsumotoK, HiroseM, ShimadaM, NaganoM, et al. (2007) LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1. Proc Natl Acad Sci U S A 104: 1859–1864.

53. HuangYS, KanMC, LinCL, RichterJD (2006) CPEB3 and CPEB4 in neurons: analysis of RNA-binding specificity and translational control of AMPA receptor GluR2 mRNA. EMBO J 25: 4865–4876.

54. HeimanM, SchaeferA, GongS, PetersonJD, DayM, et al. (2008) A translational profiling approach for the molecular characterization of CNS cell types. Cell 135: 738–748.

55. HuangY, AinsleyJA, ReijmersLG, JacksonFR (2013) Translational Profiling of Clock Cells Reveals Circadianly Synchronized Protein Synthesis. PLoS Biol 11: e1001703.

56. ThomasA, LeePJ, DaltonJE, NomieKJ, StoicaL, et al. (2012) A versatile method for cell-specific profiling of translated mRNAs in Drosophila. PLoS One 7: e40276.

57. BlauJ, YoungMW (1999) Cycling vrille expression is required for a functional Drosophila clock. Cell 99: 661–671.

58. AbruzziKC, RodriguezJ, MenetJS, DesrochersJ, ZadinaA, et al. (2011) Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression. Genes Dev 25: 2374–2386.

59. PreussF, FanJY, KaliveM, BaoS, SchuenemannE, et al. (2004) Drosophila doubletime mutations which either shorten or lengthen the period of circadian rhythms decrease the protein kinase activity of casein kinase I. Mol Cell Biol 24: 886–898.

60. MuskusMJ, PreussF, FanJY, BjesES, PriceJL (2007) Drosophila DBT lacking protein kinase activity produces long-period and arrhythmic circadian behavioral and molecular rhythms. Mol Cell Biol 27: 8049–8064.

61. McGuireSE, MaoZ, DavisRL (2004) Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci STKE 2004: pl6.

62. BoydL, ThummelCS (1993) Selection of CUG and AUG initiator codons for Drosophila E74A translation depends on downstream sequences. Proc Natl Acad Sci U S A 90: 9164–9167.

63. LinJC, HsuM, TarnWY (2007) Cell stress modulates the function of splicing regulatory protein RBM4 in translation control. Proc Natl Acad Sci U S A 104: 2235–2240.

64. LinJC, TarnWY (2009) RNA binding motif protein 4 translocates to cytoplasmic granules and suppresses translation via Argonaute2 during muscle cell differentiation. J Biol Chem

65. HasegawaM, CahillGM (2004) Regulation of the circadian oscillator in Xenopus retinal photoreceptors by protein kinases sensitive to the stress-activated protein kinase inhibitor, SB 203580. J Biol Chem 279: 22738–22746.

66. HayashiY, SanadaK, HirotaT, ShimizuF, FukadaY (2003) p38 mitogen-activated protein kinase regulates oscillation of chick pineal circadian clock. J Biol Chem 278: 25166–25171.

67. PizzioGA, HainichEC, FerreyraGA, CosoOA, GolombekDA (2003) Circadian and photic regulation of ERK, JNK and p38 in the hamster SCN. Neuroreport 14: 1417–1419.

68. VitaliniMW, de PaulaRM, GoldsmithCS, JonesCA, BorkovichKA, et al. (2007) Circadian rhythmicity mediated by temporal regulation of the activity of p38 MAPK. Proc Natl Acad Sci U S A 104: 18223–18228.

69. BayliesMK, BargielloTA, JacksonFR, YoungMW (1987) Changes in abundance or structure of the per gene product can alter periodicity of the Drosophila clock. Nature 326: 390–392.

70. BayliesMK, VosshallLB, SehgalA, YoungMW (1992) New short period mutations of the Drosophila clock gene per. Neuron 9: 575–581.

71. KonopkaRJ, Hamblen-CoyleMJ, JamisonCF, HallJC (1994) An ultrashort clock mutation at the period locus of Drosophila melanogaster that reveals some new features of the fly's circadian system. J Biol Rhythms 9: 189–216.

72. RutilaJE, EderyI, HallJC, RosbashM (1992) The analysis of new short-period circadian rhythm mutants suggests features of D. melanogaster period gene function. J Neurogenet 8: 101–113.

73. YuQ, ColotHV, KyriacouCP, HallJC, RosbashM (1987) Behaviour modification by in vitro mutagenesis of a variable region within the period gene of Drosophila. Nature 326: 765–769.

74. YuQ, JacquierAC, CitriY, HamblenM, HallJC, et al. (1987) Molecular mapping of point mutations in the period gene that stop or speed up biological clocks in Drosophila melanogaster. Proc Natl Acad Sci U S A 84: 784–788.

75. RothenfluhA, AbodeelyM, YoungMW (2000) Short-period mutations of per affect a double-time-dependent step in the Drosophila circadian clock. Curr Biol 10: 1399–1402.

76. LevineJD, FunesP, DowseHB, HallJC (2002) Signal analysis of behavioral and molecular cycles. BMC Neurosci 3: 1.