Phosphorylation of a Central Clock Transcription Factor Is Required for Thermal but Not Photic Entrainment

English version České info

Circadian clocks are synchronized to local time by daily cycles in light-dark and temperature. Although light is generally thought to be the most dominant entraining cue in nature, daily cycles in temperature are sufficient to synchronize clocks in a large range of organisms. In Drosophila, dCLOCK is a master circadian transcription factor that drives cyclical gene expression and is likely the rate-limiting component in the transcriptional/translational feedback loops that underlie the timekeeping mechanism. dCLOCK undergoes temporal changes in phosphorylation throughout a day, which is also observed for mammalian CLOCK. However, the role of CLOCK phosphorylation at the organismal level is still unclear. Using mass-spectrometry, we identified more than a dozen phosphorylation sites on dCLOCK. Blocking global phosphorylation of dCLOCK by mutating phospho-acceptor sites to alanine increases its abundance and transcriptional activity, leading to higher peak values and amplitudes in the mRNA rhythms of core clock genes, which likely explains the accelerated clock speed. Surprisingly, the clock-controlled daily activity rhythm fails to maintain synchrony with daily temperature cycles, although there is no observable defect in aligning to light/dark cycles. Our findings suggest a novel role for clock protein phosphorylation in governing the effective strengths of entraining modalities by adjusting clock amplitude.

Vyšlo v časopise: Phosphorylation of a Central Clock Transcription Factor Is Required for Thermal but Not Photic Entrainment. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004545
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004545

Souhrn

Zdroje

1. AlladaR, ChungBY (2010) Circadian organization of behavior and physiology in Drosophila. Annu Rev Physiol 72 : 605–624.

2. ZhangEE, KaySA (2010) Clocks not winding down: unravelling circadian networks. Nat Rev Mol Cell Biol 11 : 764–776.

3. Hastings JW, Rusak B, Boulos Z (1991) Circadian rhythms: the physiology of biological timing; L PC, editor. USA: New York : Wiley-Liss, c1991.

4. YoshiiT, HermannC, Helfrich-ForsterC (2010) Cryptochrome-positive and -negative clock neurons in Drosophila entrain differentially to light and temperature. J Biol Rhythms 25 : 387–398.

5. BaeK, LeeC, HardinPE, EderyI (2000) dCLOCK is present in limiting amounts and likely mediates daily interactions between the dCLOCK-CYC transcription factor and the PER-TIM complex. J Neurosci 20 : 1746–1753.

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

7. CyranSA, BuchsbaumAM, ReddyKL, LinMC, GlossopNR, et al. (2003) vrille, Pdp1, and dClock form a second feedback loop in the Drosophila circadian clock. Cell 112 : 329–341.

8. GlossopNR, HoulJH, ZhengH, NgFS, DudekSM, et al. (2003) VRILLE feeds back to control circadian transcription of Clock in the Drosophila circadian oscillator. Neuron 37 : 249–261.

9. PartchCL, GreenCB, TakahashiJS (2014) Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24 : 90–99.

10. BaeK, EderyI (2006) Regulating a circadian clock's period, phase and amplitude by phosphorylation: insights from Drosophila. J Biochem 140 : 609–617.

11. DiernfellnerAC, SchafmeierT (2011) Phosphorylations: Making the Neurosporacrassa circadian clock tick. FEBS Lett 585 : 1461–1466.

12. GallegoM, VirshupDM (2007) Post-translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8 : 139–148.

13. MehraA, BakerCL, LorosJJ, DunlapJC (2009) Post-translational modifications in circadian rhythms. Trends Biochem Sci 34 : 483–490.

14. ReischlS, KramerA (2011) Kinases and phosphatases in the mammalian circadian clock. FEBS Lett 585 : 1393–1399.

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

16. 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.

17. CyranSA, YiannoulosG, BuchsbaumAM, SaezL, YoungMW, et al. (2005) The double-time protein kinase regulates the subcellular localization of the Drosophila clock protein period. J Neurosci 25 : 5430–5437.

18. GarbeDS, FangY, ZhengX, SowcikM, AnjumR, et al. (2013) Cooperative interaction between phosphorylation sites on PERIOD maintains circadian period in Drosophila. PLoS Genet 9: e1003749.

19. 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.

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

21. 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.

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

23. 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.

24. MartinekS, InonogS, ManoukianAS, YoungMW (2001) A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105 : 769–779.

25. LinJM, KilmanVL, KeeganK, PaddockB, Emery-LeM, et al. (2002) A role for casein kinase 2alpha in the Drosophila circadian clock. Nature 420 : 816–820.

26. AktenB, JauchE, GenovaGK, KimEY, EderyI, et al. (2003) A role for CK2 in the Drosophila circadian oscillator. Nat Neurosci 6 : 251–257.

27. YuW, HoulJH, HardinPE (2011) NEMO kinase contributes to core period determination by slowing the pace of the Drosophila circadian oscillator. Curr Biol 21 : 756–761.

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

29. 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.

30. 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.

31. 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.

32. WeberF, HungHC, MaurerC, KaySA (2006) Second messenger and Ras/MAPK signalling pathways regulate CLOCK/CYCLE-dependent transcription. J Neurochem 98 : 248–257.

33. SzaboA, PapinC, ZornD, PonienP, WeberF, et al. (2013) The CK2 kinase stabilizes CLOCK and represses its activity in the Drosophila circadian oscillator. PLoS Biol 11: e1001645.

34. LeeC, EtchegarayJP, CagampangFR, LoudonAS, ReppertSM (2001) Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107 : 855–867.

35. KondratovRV, ChernovMV, KondratovaAA, GorbachevaVY, GudkovAV, et al. (2003) BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev 17 : 1921–1932.

36. YoshitaneH, TakaoT, SatomiY, DuNH, OkanoT, et al. (2009) Roles of CLOCK phosphorylation in suppression of E-box-dependent transcription. Mol Cell Biol 29 : 3675–3686.

37. SpenglerML, KuropatwinskiKK, SchumerM, AntochMP (2009) A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation. Cell Cycle 8 : 4138–4146.

38. TischkauSA, MitchellJW, PaceLA, BarnesJW, BarnesJA, et al. (2004) Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock. Neuron 43 : 539–549.

39. ShimHS, KimH, LeeJ, SonGH, ChoS, et al. (2007) Rapid activation of CLOCK by Ca2+-dependent protein kinase C mediates resetting of the mammalian circadian clock. EMBO Rep 8 : 366–371.

40. KoHW, KimEY, ChiuJ, VanselowJT, KramerA, et al. (2010) A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks. J Neurosci 30 : 12664–12675.

41. SchlosserA, VanselowJT, KramerA (2005) Mapping of phosphorylation sites by a multi-protease approach with specific phosphopeptide enrichment and NanoLC-MS/MS analysis. Anal Chem 77 : 5243–5250.

42. KadenerS, MenetJS, SchoerR, RosbashM (2008) Circadian transcription contributes to core period determination in Drosophila. PLoS Biol 6: e119.

43. ZhaoJ, KilmanVL, KeeganKP, PengY, EmeryP, et al. (2003) Drosophila clock can generate ectopic circadian clocks. Cell 113 : 755–766.

44. PittendrighCS (1954) on temperature independence in the clock system controlling emergence time in drosophila. Proc Natl Acad Sci U S A 40 : 1018–1029.

45. LeeC, BaeK, EderyI (1998) The Drosophila CLOCK protein undergoes daily rhythms in abundance, phosphorylation, and interactions with the PER-TIM complex. Neuron 21 : 857–867.

46. KimEY, BaeK, NgFS, GlossopNR, HardinPE, et al. (2002) Drosophila CLOCK protein is under posttranscriptional control and influences light-induced activity. Neuron 34 : 69–81.

47. AshmoreLJ, SehgalA (2003) A fly's eye view of circadian entrainment. J Biol Rhythms 18 : 206–216.

48. ChenY, Hunter-EnsorM, SchotlandP, SehgalA (1998) Alterations of per RNA in noncoding regions affect periodicity of circadian behavioral rhythms. J Biol Rhythms 13 : 364–379.

49. RensingL, RuoffP (2002) Temperature effect on entrainment, phase shifting, and amplitude of circadian clocks and its molecular bases. Chronobiol Int 19 : 807–864.

50. BuszaA, MuradA, EmeryP (2007) Interactions between circadian neurons control temperature synchronization of Drosophila behavior. J Neurosci 27 : 10722–10733.

51. GlaserFT, StanewskyR (2005) Temperature synchronization of the Drosophila circadian clock. Curr Biol 15 : 1352–1363.

52. WheelerDA, Hamblen-CoyleMJ, DushayMS, HallJC (1993) Behavior in light-dark cycles of Drosophila mutants that are arrhythmic, blind, or both. J Biol Rhythms 8 : 67–94.

53. YoshiiT, HeshikiY, Ibuki-IshibashiT, MatsumotoA, TanimuraT, et al. (2005) Temperature cycles drive Drosophila circadian oscillation in constant light that otherwise induces behavioural arrhythmicity. Eur J Neurosci 22 : 1176–1184.

54. YoshiiT, SakamotoM, TomiokaK (2002) A temperature-dependent timing mechanism is involved in the circadian system that drives locomotor rhythms in the fruit fly Drosophila melanogaster. Zoolog Sci 19 : 841–850.

55. SoWV, RosbashM (1997) Post-transcriptional regulation contributes to Drosophila clock gene mRNA cycling. EMBO J 16 : 7146–7155.

56. EderyI (2011) A master CLOCK hard at work brings rhythm to the transcriptome. Genes Dev 25 : 2321–2326.

57. LamazeA, LamourouxA, ViasC, HungHC, WeberF, et al. (2011) The E3 ubiquitin ligase CTRIP controls CLOCK levels and PERIOD oscillations in Drosophila. EMBO Rep 12 : 549–557.

58. HeQ, ChaJ, HeQ, LeeHC, YangY, et al. (2006) CKI and CKII mediate the FREQUENCY-dependent phosphorylation of the WHITE COLLAR complex to close the Neurospora circadian negative feedback loop. Genes Dev 20 : 2552–2565.

59. SchafmeierT, HaaseA, KaldiK, ScholzJ, FuchsM, et al. (2005) Transcriptional feedback of Neurospora circadian clock gene by phosphorylation-dependent inactivation of its transcription factor. Cell 122 : 235–246.

60. EideEJ, VielhaberEL, HinzWA, VirshupDM (2002) The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon. J Biol Chem 277 : 17248–17254.

61. SanadaK, OkanoT, FukadaY (2002) Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1. J Biol Chem 277 : 267–271.

62. PittendrighC, BruceV, KausP (1958) on the significance of transients in daily rhythms. Proc Natl Acad Sci U S A 44 : 965–973.

63. LiuY, MerrowM, LorosJJ, DunlapJC (1998) How temperature changes reset a circadian oscillator. Science 281 : 825–829.

64. BrownSA, ZumbrunnG, Fleury-OlelaF, PreitnerN, SchiblerU (2002) Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr Biol 12 : 1574–1583.

65. LahiriK, ValloneD, GondiSB, SantorielloC, DickmeisT, et al. (2005) Temperature regulates transcription in the zebrafish circadian clock. PLoS Biol 3: e351.

66. MatsumotoA, MatsumotoN, HaruiY, SakamotoM, TomiokaK (1998) Light and temperature cooperate to regulate the circadian locomotor rhythm of wild type and period mutants of Drosophila melanogaster. J Insect Physiol 44 : 587–596.

67. GentileC, SehadovaH, SimoniA, ChenC, StanewskyR (2013) Cryptochrome antagonizes synchronization of Drosophila's circadian clock to temperature cycles. Curr Biol 23 : 185–195.

68. VinayakP, CouparJ, HughesSE, FozdarP, KilbyJ, et al. (2013) Exquisite light sensitivity of Drosophila melanogaster cryptochrome. PLoS Genet 9: e1003615.

69. Lakin-ThomasPL, BrodyS, CoteGG (1991) Amplitude model for the effects of mutations and temperature on period and phase resetting of the Neurospora circadian oscillator. J Biol Rhythms 6 : 281–297.

70. PittendrighCS, KynerWT, TakamuraT (1991) The amplitude of circadian oscillations: temperature dependence, latitudinal clines, and the photoperiodic time measurement. J Biol Rhythms 6 : 299–313.

71. AbrahamU, GranadaAE, WestermarkPO, HeineM, KramerA, et al. (2010) Coupling governs entrainment range of circadian clocks. Mol Syst Biol 6 : 438.

72. VitaternaMH, KoCH, ChangAM, BuhrED, FruechteEM, et al. (2006) The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude. Proc Natl Acad Sci U S A 103 : 9327–9332.

73. DallmannR, DeBruyneJP, WeaverDR (2011) Photic resetting and entrainment in CLOCK-deficient mice. J Biol Rhythms 26 : 390–401.

74. Winfree AT (2001) The Geometry of Biological Time: Springer.

75. ChangDC, ReppertSM (2003) A novel C-terminal domain of drosophila PERIOD inhibits dCLOCK:CYCLE-mediated transcription. Curr Biol 13 : 758–762.

76. GolicKG, GolicMM (1996) Engineering the Drosophila genome: chromosome rearrangements by design. Genetics 144 : 1693–1711.

77. ParksAL, CookKR, BelvinM, DompeNA, FawcettR, et al. (2004) Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome. Nat Genet 36 : 288–292.

78. ThibaultST, SingerMA, MiyazakiWY, MilashB, DompeNA, et al. (2004) A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat Genet 36 : 283–287.

79. VenkenKJ, HeY, HoskinsRA, BellenHJ (2006) P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science 314 : 1747–1751.

80. GrothAC, FishM, NusseR, CalosMP (2004) Construction of transgenic Drosophila by using the site-specific integrase from phage phiC31. Genetics 166 : 1775–1782.