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sexta-feira, junho 16, 2017

Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation

Masatoshi Hara Boryana Petrova Terry L Orr-Weaver Is a corresponding author

Whitehead Institute and Massachusetts Institute of Technology, United States Massachusetts Institute of Technology, United States



The oocyte-to-embryo transition involves extensive changes in mRNA translation, regulated in Drosophila by the PNG kinase complex whose activity we show here to be under precise developmental control. Despite presence of the catalytic PNG subunit and the PLU and GNU activating subunits in the mature oocyte, GNU is phosphorylated at Cyclin B/CDK1sites and unable to bind PNG and PLU. In vitro phosphorylation of GNU by CyclinB/CDK1 blocks activation of PNG. Meiotic completion promotes GNU dephosphorylation and PNG kinase activation to regulate translation. The critical regulatory effect of phosphorylation is shown by replacement in the oocyte with a phosphorylation-resistant form of GNU, which promotes PNG-GNU complex formation, elevation of Cyclin B, and meiotic defects consistent with premature PNG activation. After PNG activation GNU is destabilized, thus inactivating PNG. This short-lived burst in kinase activity links development with maternal mRNA translation and ensures irreversibility of the oocyte-to-embryo transition.

eLife digest

New egg cells form via a specialized kind of cell division called called meiosis, and will pause at key stages in this process before continuing their development. One of these pauses occurs before the egg cell is fertilized. At fertilization, the egg cell becomes “activated”, development resumes, and it starts forming into an embryo. Molecules deposited in the egg cell when it originally formed are used to control these earliest stages of embryonic development. These molecules include messenger RNA molecules (mRNAs for short), which can be “translated” to build proteins.

In fruit flies, an enzyme called PNG kinase regulates the translation of hundreds of mRNA molecules during the period after the pause, when the maturing egg cell is activated and the embryo begins to develop. It is not well understood what activates and inactivates the kinase to limit its activity to this period of time. However, it was known that a protein called GNU was needed to bind to the PNG kinase to make it active.

CyclinB/CDK1 is another kinase, and in contrast to PNG it is highly active when the egg cell is paused. When the egg cell is activated for embryonic development, the levels of this second kinase drop sharply and meiosis is completed. Like all kinases, CyclinB/CDK1 attaches phosphate groups onto other molecules, and Hara et al. now show that CyclinB/CDK1 can modify the GNU protein in this way. The added phosphate groups prevent GNU from binding to the PNG kinase, meaning that the high levels of CyclinB/CDK1 during the pause stop GNU from activating the PNG kinase. However, when the egg cell is activated, the level of CyclinB/CDK1 declines so that there are not enough of these molecules to add phosphates onto GNU. This leaves GNU free to activate the PNG kinase, allowing this kinase to control the translation of mRNA molecules. Furthermore, the activity of PNG kinase leads to the destruction of GNU, and this feedback loop limits this kinase’s activity to the narrow window of time in which it is needed.

The fruit fly is the second example of an animal in which the activity of a kinase essential for embryonic development has been linked to the completion of meiosis (the other being the roundworm Caenorhabditis elegans). The use of this strategy in two such different animals suggests that it may also be common to many other animals, including humans. Further investigation is now needed to determine if this is indeed the case.