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  The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization

Korge, S., Maier, B., Brüning, F., Ehrhardt, L., Korte, T., Mann, M., et al. (2018). The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization. PLoS Genetics, 14(1): e1007189. doi:10.1371/journal.pgen.1007189.

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 Creators:
Korge, Sandra1, Author
Maier, Bert1, Author
Brüning, Franziska2, Author              
Ehrhardt, Lea1, Author
Korte, Thomas1, Author
Mann, Matthias2, Author              
Herrmann, Andreas1, Author
Robles, Maria S.1, Author
Kramer, Achim1, Author
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1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: KINASE-I-EPSILON; CLOCK PROTEINS; COMPUTATIONAL PLATFORM; MAMMALIAN-CELLS; PERIOD PROTEINS; NEGATIVE LIMB; CKI-EPSILON; ENTRY; DYNAMICS; ROLESGenetics & Heredity;
 Abstract: Circadian clocks are molecular timekeeping mechanisms that allow organisms to anticipate daily changes in their environment. The fundamental cellular basis of these clocks is delayed negative feedback gene regulation with PERIOD and CRYPTOCHROME containing protein complexes as main inhibitory elements. For a correct circadian period, it is essential that such clock protein complexes accumulate in the nucleus in a precisely timed manner, a mechanism that is poorly understood. We performed a systematic RNAi-mediated screen in human cells and identified 15 genes associated with the nucleo-cytoplasmic translocation machinery, whose expression is important for circadian clock dynamics. Among them was Transportin 1 (TNPO1), a non-classical nuclear import carrier, whose knockdown and knockout led to short circadian periods. TNPO1 was found in endogenous clock protein complexes and particularly binds to PER1 regulating its (but not PER2's) nuclear localization. While PER1 is also transported to the nucleus by the classical, Importin beta-mediated pathway, TNPO1 depletion slowed down PER1 nuclear import rate as revealed by fluorescence recovery after photobleaching (FRAP) experiments. In addition, we found that TNPO1-mediated nuclear import may constitute a novel input pathway of how cellular redox state signals to the clock, since redox stress increases binding of TNPO1 to PER1 and decreases its nuclear localization. Together, our RNAi screen knocking down import carriers (but also export carriers) results in short and long circadian periods indicating that the regulatory pathways that control the timing of clock protein subcellular localization are far more complex than previously assumed. TNPO1 is one of the novel players essential for normal circadian periods and potentially for redox regulation of the clock.

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Language(s): eng - English
 Dates: 2018-01-29
 Publication Status: Published online
 Pages: 23
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 Table of Contents: -
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Title: PLoS Genetics
  Other : PLoS Genet.
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 14 (1) Sequence Number: e1007189 Start / End Page: - Identifier: ISSN: 1553-7390
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000017180