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TIM Binds Importin α1, and Acts as an Adapter to Transport PER to the Nucleus

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In Drosophila, circadian rhythms are driven by a negative feedback loop that includes the key regulators, period (per) and timeless (tim). To generate this feedback loop, PER and TIM proteins first accumulate in the cytoplasm and then translocate to the nucleus where PER represses transcription. Thus, the nuclear import of PER-TIM proteins is a critical step to separate the phases of activation and repression of mRNA synthesis. In this study, we discovered that a member of the nuclear import machinery, importin α1 is an essential component of this feedback loop. Flies lacking importin α1 (IMPα1) display arrhythmic behavior and cytoplasmic expression of both PER and TIM at all times. In cultured S2 cells, IMPα1 expression directly facilitates nuclear import of TIM, but the effect on PER appears to be indirect. TIM expression is detected at the nuclear envelope and it interacts with other components of the nuclear transport machinery, which we show are also required for nuclear expression of TIM-PER and for behavioral rhythms. Our results thus suggest that TIM functions to link PER to the nuclear import machinery through IMPα1. Altogether, this study provides the mechanistic basis of a crucial step in the circadian clock mechanism.

Vyšlo v časopise: TIM Binds Importin α1, and Acts as an Adapter to Transport PER to the Nucleus. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004974
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004974

Souhrn

In Drosophila, circadian rhythms are driven by a negative feedback loop that includes the key regulators, period (per) and timeless (tim). To generate this feedback loop, PER and TIM proteins first accumulate in the cytoplasm and then translocate to the nucleus where PER represses transcription. Thus, the nuclear import of PER-TIM proteins is a critical step to separate the phases of activation and repression of mRNA synthesis. In this study, we discovered that a member of the nuclear import machinery, importin α1 is an essential component of this feedback loop. Flies lacking importin α1 (IMPα1) display arrhythmic behavior and cytoplasmic expression of both PER and TIM at all times. In cultured S2 cells, IMPα1 expression directly facilitates nuclear import of TIM, but the effect on PER appears to be indirect. TIM expression is detected at the nuclear envelope and it interacts with other components of the nuclear transport machinery, which we show are also required for nuclear expression of TIM-PER and for behavioral rhythms. Our results thus suggest that TIM functions to link PER to the nuclear import machinery through IMPα1. Altogether, this study provides the mechanistic basis of a crucial step in the circadian clock mechanism.

Zdroje

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