Metabolic Control of Oocyte Apoptosis Mediated by 14-3-3zeta-regulated Dephosphorylation of Caspase-2

Rafael Fissore, University of Massachusetts - Amherst
L.K. Nutt
M.R. Buchakjian
E. Gan
R. Darbandi
S.Y. Yoon
J.Q. Wu
Y.J. Miyamoto
J.A. Gibbons
J.L. Andersen
C.D. Freel
W. Tang
C. He
M. Kurokawa
Y. Wang
S.S. Margolis
S. Kornbluth

Abstract

Xenopus oocyte death is partly controlled by the apoptotic initiator caspase-2 (C2). We reported previously that oocyte nutrient depletion activates C2 upstream of mitochondrial cytochrome c release. Conversely, nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. Although C2 dephosphorylation is responsive to metabolism, neither PP1 activity nor binding is metabolically regulated. Rather, release of 14-3-3zeta from C2 is controlled by metabolism and allows for C2 dephosphorylation. Accordingly, a C2 mutant unable to bind 14-3-3zeta is highly susceptible to dephosphorylation. Although this mechanism was initially established in Xenopus, we now demonstrate similar control of murine C2 by phosphorylation and 14-3-3 binding in mouse eggs. These findings provide an unexpected evolutionary link between 14-3-3 and metabolism in oocyte death.