Abstract
mRNA decapping is a central step in eukaryotic mRNA decay that simultaneously shuts down translation initiation and activates mRNA degradation. A major complex responsible for decapping consists of the decapping enzyme Dcp2 in association with decapping enhancers. An important question is how the activity and accumulation of Dcp2 are regulated at the cellular level to ensure the specificity and fidelity of the Dcp2 decapping complex. Here, we show that human Dcp2 levels and activity are controlled by a competition between decapping complex assembly and Dcp2 degradation. This is mediated by a regulatory domain in the Dcp2 C terminus, which, on the one hand, promotes Dcp2 activation via decapping complex formation mediated by the decapping enhancer Hedls and, on the other hand, targets Dcp2 for ubiquitin-mediated proteasomal degradation in the absence of Hedls association. This competition between Dcp2 activation and degradation restricts the accumulation and activity of uncomplexed Dcp2, which may be important for preventing uncontrolled decapping or for regulating Dcp2 levels and activity according to cellular needs.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01517-14.
ACKNOWLEDGMENTS
This work was supported by grant R01 GM077243 from the National Institutes of Health to J.L.-A. S.L.E. was supported by National Institutes of Health Institutional Training Grant in Signaling and Cellular Regulation no. T32 GM08759.
We thank Min Han for use of the fluorescence microscope and Megerditch Kiledjian for the anti-Dcp2 and anti-Nudt16 antibodies. We thank the J. Lykke-Andersen lab for helpful discussions; in particular, we thank Sebastien Durand and Rea Lardelli for critical comments on the manuscript.