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Abstract
The RNA binding protein CPEB (cytoplasmic polyadenylation element binding) regulates cytoplasmic polyadenylation and translation in germ cells and the brain. In neurons, CPEB is detected at postsynaptic sites, as well as in the cell body. The related CPEB3 protein also regulates translation in neurons, albeit probably not through polyadenylation; it, as well as CPEB4, is present in dendrites and the cell body. Here, we show that treatment of neurons with ionotropic glutamate receptor agonists causes CPEB4 to accumulate in the nucleus. All CPEB proteins are nucleus-cytoplasm shuttling proteins that are retained in the nucleus in response to calcium-mediated signaling and alpha-calcium/calmodulin-dependent kinase protein II (CaMKII) activity. CPEB2, -3, and -4 have conserved nuclear export signals that are not present in CPEB. CPEB4 is necessary for cell survival and becomes nuclear in response to focal ischemia in vivo and when cultured neurons are deprived of oxygen and glucose. Further analysis indicates that nuclear accumulation of CPEB4 is controlled by the depletion of calcium from the ER, specifically, through the inositol-1,4,5-triphosphate (IP3) receptor, indicating a communication between these organelles in redistributing proteins between subcellular compartments.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank Lan Xu for advice on the in vitro nuclear import assay, Oswald Steward for providing rat brain sections, and Melissa Jungnickel and Keith Sutton for help with the calcium fluorescence assays. We also thank the UMass Medical School imaging facility and the electron microscopy core facility, Robert Singer for the N-EGFP-MS2 plasmid, Roger Tsien for the Cameleon D1ER plasmid, Arthur Mercurio for the use of his hypoxia chamber, and Rachel Groppo for reading the manuscript.
This work was supported by grants from the NIH (GM46779 and HD37267). A.C.-M. was supported by grant number 3 R01 GM046779-19S1. Core support from the Diabetes and Endocrinology Research Center Program Project (DK32520) is gratefully acknowledged.