CPEB4 Is a Cell Survival Protein Retained in the Nucleus upon Ischemia or Endoplasmic Reticulum Calcium Depletion

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.The cytoplasmic polyadenylation element binding (CPEB) protein, a sequence-specific RNA binding protein, is found in the cell body and at synapses of hippocampal and other neurons; in response to synaptic experience, CPEB promotes polyadenylation and translation (37,49,50). CPEB knockout mice (44) have deficiencies in synaptic plasticity, particularly, theta burst-induced long-term potentiation (LTP) (1, 51), as well as in particular forms of hippocampal-dependent memories (3). Some of these CPEB-related functions may be related at least in part to its ability to direct CPE-containing RNA transport in dendrites (16), in addition to its regulation of translation (51).In neurons, most of the CPEB-related proteins CPEB3 and CPEB4 are found in the cell soma. However, a relatively small amount of these proteins is localized to synaptic regions and cofractionates with postsynaptic density (PSD) proteins, suggesting possible roles in RNA translation and/or localization (17). While investigating the possible translocation of CPEB3 and -4 to dendritic spines in response to N-methyl-D-aspartate receptor (NMDAR) activation, as is the case with the fragile X mental retardation protein (FMRP) (11), we noticed a surprising relocalization of CPEB4 from the cell soma to the nucleus. While the treatment of neurons with ionotropic glutamate receptor-activating agents, such as glutamate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), as well as NMDA, induced nuclear localization of CPEB4, 3,5-dihydroxyphenylglycine (DHPG), an agonist of the metabotropic glutamate receptors, did not. CPEB4 remained cytoplasmic when calcium/calmodulin-dependent protein kinase II (CaMKII) activity was inhibited, suggesting a link between calcium levels and nuclear i...

mRNA trafficking and local translation: the Yin and Yang of regulating mRNA localization in neurons

“…Proteins such as Staufen1 and Staufen2, Translin and Trax, Nova, the ELAV families of proteins as well as numerous other RBPs have been linked to local translation or trafficking, directly or indirectly, in neurons as well as other cell types [77][78][79][80][81][82]. Three other paralogous CPEB proteins (CPEB2, CPEB3, and CPEB4) are also conserved, and expressed in the nervous system [83][84][85]. The available evidence suggests that these proteins are probably not functionally equivalent to CPEB1 despite their similarity and they may mediate translational repression by a different mechanism [86].…”

A fly trap mechanism provides sequence-specific RNA recognition by CPEB proteins

“…Additionally, potential nuclear localization and nuclear export signals are present within the same domain as well (Ernoult-Lange et al 2009;Lin et al 2010). Although much less is known about the other members of the family (CPEB2-4), their N-terminal domains also appear to contain nuclear import and export signals (Kan et al 2010) and regulatory phosphorylation sites (Igea and Mendez 2010).…”

Endoplasmic reticulum stress in brain ischemia

“…The research has shown that CPEB4 nuclear accumulation provides protection which is due to the depletion of the ER Ca 2+ store rather than the increase of Ca 2+ in cytoplasm. In addition, IP 3 R, rather than RyR, is responsible for the CPEB4 nuclear import [51]. This elegant experiment highlights that although ER stress induces Ca 2+ loss, the redistribution of CPEB4 between organelles reduces ischemic damage (Figure 2).…”

“…CPEB4 (cytoplasmic polyadenylation element binding 4) is a typical example. The CPEB family mainly participates in the events of cytoplasmic polyadenylation, translation and RNA transport, but most important are their nucleus-cytoplasm shuttling characteristics [50,51]. In normal conditions, the CPEB4 is located in dendrites and the cell body; while in the rat cerebral ischemia model CPEB4 was found abundantly in the nucleus of penumbra, further suggesting the shuttling feature of CPEB4.…”

“…During the conditions of ER stress, aggregated STIMs interact with ORAI and drive Ca 2+ into the cytosol. Moreover, subsequent uptake of the influxed Ca 2+ , by the ER though the SERCA, assists in maintaining cell homeostasis [51,59] (Figure 2). …”