Control of the pericentrosomal H2O2 level by peroxiredoxin I is critical for mitotic progression

Abstract

Proteins associated with the centrosome play key roles in mitotic progression in mammalian cells. The activity of Cdkl-opposing phosphatases at the centrosome must be inhibited during early mitosis to prevent premature dephosphorylation of Cdhl-an activator of the ubiquitin ligase anaphase-promoting complex/cyclosome and the consequent premature degradation of mitotic activators. In this paper, we show that reversible oxidative inactivation of centrosome-bound protein phosphatases such as Cdcl 4B by H2O2 is likely responsible for this inhibition. The intracellular concentration of H2O2 increases as the cell cycle progresses. Whereas the centrosome is shielded from H2O2 through its association with the H2O2-eliminating enzyme peroxiredoxin I (Prxl) during interphase, the centrosome-associated Prxl is selectively inactivated through phosphorylation by Cdkl during early mitosis, thereby exposing the centrosome to H2O2 and facilitating inactivation of centrosome-bound phosphatases. Dephosphorylation of Prxl by okadaic acid sensitive phosphatases during late mitosis again shields the centrosome from H2O2 and thereby allows the reactivation of Cdkl-opposing phosphatases at the organelle.