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Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
Received 9 August 2005/ Returned for modification 16 September 2005/ Accepted 27 September 2005
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ABSTRACT |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The synaptodendritic compartment of hippocampal and other neurons contains CPEB and several of the polyadenylation/translation factors noted above (22, 42). The cytoplasmic polyadenylation machinery is activated by N-methyl-D-aspartate receptors (NMDARs) and results in CPEB phosphorylation, polyadenylation, and translation of several CPE-containing mRNAs (11, 22, 41, 42). Ablation of CPEB in either knockout mice or in antisense oligonucleotide-treated Aplysia neurons results in defects in synaptic plasticity (2, 38).
To investigate additional CPEB activities in neurons and possibly other cells, a yeast two-hybrid screen with a mouse brain cDNA library as the prey was performed. Surprisingly, amyloid precursor-like protein 1 (APLP1) was found to be a CPEB-interacting factor. APLP1 and the related amyloid precursor protein (APP) and APLP2 are large plasma membrane-spanning proteins that have small carboxy-terminal intracellular domains (ICDs) (40). Several additional experiments including in vitro and in vivo coimmunoprecipitation, glutathione S-transferase (GST) pulldowns, and immunocytochemistry confirm these interactions. The ICDs, which can be cleaved from the remainder of the membrane-anchored proteins by the 
-secretase/presenilin system, are the portions that bind CPEB. The ICDs interact with a number of cytoplasmic proteins (40); in addition, they may be transported to the nucleus to activate transcription (10). In oocytes, the most efficacious system for examining CPEB activity, the APPs stimulate CPEB S174 phosphorylation, polyadenylation, and translational activation. The ICDs are necessary and sufficient for these activities.
While the ICDs are essential for the CPEB activities noted above, it is not necessary for them to be cleaved from the remainder of the protein. Indeed, sucrose gradient fractionation of oocyte extracts reveals that a substantial portion of CPEB cosediments with full-length APLP1, which also cosediments with Na/K ATPase, a marker for plasma membranes. In these fractions, not only does CPEB coimmunoprecipitate with APLP1, but immunoelectron microscopy demonstrates that both are membrane associated. Other members of the polyadenylation/translation complex (Maskin, eIF4E, Aurora A, Gld-2, and symplekin) also cofractionate with APLP1 to various extents; the proteins reside in a complex in these fractions. Most cytoplasmic polyadenylation occurs in the APLP1-containing fractions, where CPE-containing RNA can be found in association with membranes. Immunoelectron microscopy of sectioned oocytes shows that APLP1, CPEB, Maskin, Gld-2, and Aurora A are all associated with membranes. In cultured hippocampal neurons, CPEB and APLP1 also colocalize and transfected APLP1-ICD stimulates translation in a CPE-dependent manner. These data demonstrate that the ICDs of APP family member proteins not only anchor the cytoplasmic polyadenylation machinery to membranes but also stimulate 3' end processing and translation. Such results have important implications for oocyte development and synaptic activity, both of which are regulated by CPEB.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C) cloned into the NcoI-BamHI site of pGBKT7 vector (bait) and a mouse brain cDNA library cloned into the pACT2 vector (prey) were used in yeast two-hybrid assays (Clontech), which yielded several positives that encoded the carboxy-terminal region of APLP1. Full-length clones encoding APLP1, APLP2, and APP, myc-tagged at their carboxy termini, were provided by R. Homayouni (University of Tennessee Health Center, Memphis) (20). These and additional clones were used as templates for PCR (APLP amino acid residues 1 to 650, 1 to 606, 495 to 650, and 600 to 650; APLP2 residues 1 to 763; and APP residues 1 to 695, 1 to 638, and 595 to 695) for cloning into the ClaI-XhoI or ClaI-BamHI sites of pGADT7. Mouse CPEBC was cloned into pGEX-KG; green fluorescent protein (GFP)-CPEB has been described previously (21). Protein-protein interaction assays. In addition to yeast two-hybrid assays, additional protein-protein interaction experiments were conducted. Cos-7 cells were transfected with DNAs encoding APLP1-myc and GFP-CPEB, using Effectene (QIAGEN). After 40 h of expression, the cells were washed three times with phosphate-buffered saline (PBS) and lysed in TX-LB (150 mM NaCl; 30 mM HEPES, pH 7.5; 5 mM MgCl2; 1 mM EGTA; 1% Triton X-100; 10% glycerol; 1 mM sodium vanadate; 25 mM sodium fluoride; 2 mM phenylmethylsulfonyl fluoride; 10 µg/ml each of aprotinin, leupeptin, pepstatin, and trypsin inhibitor; and 0.1% 2-mercaptoethanol) (20). Protein A-Sepharose beads conjugated with either myc antibody or nonspecific immunoglobulin G (IgG) were then added to the lysate, which was made up to a radioimmunoprecipitation assay (RIPA) buffer (150 mM NaCl, 1% NP-40, 0.5% deoxycholate, 0.1% sodium dodecyl sulfate [SDS], 50 mM Tris, pH 8). After 1 h of mixing at 4°C, the beads were washed extensively with 1x RIPA and the beads were then boiled in SDS sample buffer.
Plasmids encoding CPEB, CPEBC, APLP1, APLP-ICD, APLP2, and APP were transcribed and translated in vitro with a TNT T3/T7 coupled reticulocyte lysate system (Promega) in the presence of [35S]methionine and [35S]cysteine. Lysates containing various combinations of the synthesized proteins were mixed and subjected to immunoprecipitation with CPEB antibody or nonspecific IgG coupled to protein A-Sepharose. APLP1-myc mRNA was injected into Xenopus ooyctes (
1 ng/nl, 30 nl/oocyte), which were incubated for 12 h before lysis and immunoprecipitation with myc antibody (39). A Western blot of the immunoprecipitate was probed for CPEB.
A mouse brain extract was centrifuged to remove insoluble material and applied to the CPEBC-GST column or a column containing GST only. The beads were washed in RIPA buffer and eluted with SDS buffer; a Western blot was probed for APP and APLP1.
Polyadenylation and CPEB phosphorylation assays.
Xenopus oocytes were injected with mRNAs encoding APLP1, APLP1-ICD, APLP1-ICD, APP, or APP-ICD (1 ng/nl, 30 nl/oocyte) and incubated overnight. The oocytes were then injected with 32P-labeled CPE-containing 3' UTR of cyclin B1 RNA (9) and incubated for a further 0 to 6 h in the presence of progesterone (10 ng/ml or 100 ng/ml). The RNA was extracted at various times and analyzed by polyacrylamide gel electrophoresis (PAGE). Extracts from mRNA-injected oocytes were also probed on Western blots with myc antibody.
For the phosphorylation assays, oocytes were injected with mRNA encoding APLP1 and then incubated for 8 h. The oocytes were then incubated with 10 ng/ml progesterone and cultured for a further 4 or 6 h. Extracts were then prepared by homogenizing 5 oocytes each in H1 (cdk1) kinase buffer (80 mM Na ß-glycerophosphate, 20 mM EGTA, 15 mM MgCl2, 50 mM NaVaO4) plus protease inhibitors (10 µg/ml each of pepstatin, leupeptin, and aprotinin) and then pelleting insoluble material by centrifugation for 5 min at 15,000 x g at 4°C. The phosphorylation reaction mixture also contained 20 µl of oocyte extract, 30 µM [-32P]ATP (0.16 mCi/ml), and 0.5 µg of Escherichia coli-expressed CPEBC or CPEBC with an S174A mutation. The assays were performed in a 40-µl volume in reaction buffer containing a final concentration of 20 mM Tris, pH 7.7, 10 mM MgCl2, 50 mM KCl, and 1 mM dithiothreitol. The proteins were then analyzed by SDS-PAGE and processed for two-dimensional phosphopeptide mapping following tosylphenylalanyl chloromethyl ketone (TPCK)-treated trypsin digestion (29).
CAT assays.
Oocytes were injected with mRNAs encoding myc-tagged APLP1, APLP1-ICD, APLP1ICD, or APP (equal molar), incubated overnight, and injected with mRNAs encoding chloramphenicol acetyltransferase (CAT) with 3' UTRs containing or lacking the CPE and AAUAAA. The oocytes were treated with 10 ng/ml progesterone and collected at various times thereafter. CAT assays were performed as described previously (9).
Sucrose gradient fractionation, coimmunoprecipitation, and immunoelectron microscopy. Fifty to 100 oocytes were homogenized in 0.5 ml of HB buffer (10% sucrose, 20 mM Tris, pH 7.6, 50 mM KCl, 10 mM MgCl2, 0.3 M NaCl, 2 mM EDTA, protease inhibitor cocktail from Roche), layered onto 10 ml of 20 to 60% linear sucrose gradients (24), centrifuged in a Beckman SW41 Ti rotor at 36,000 rpm for 15 h at 4C, and collected in 0.5-ml fractions. The protein was precipitated by 7% trichloroacetic acid, the pellets were washed in cold acetone and dissolved in 8 M urea, and then one-third of the sample was analyzed by SDS-PAGE and Western blotting. For some experiments, specific fractions were combined, dialyzed against HB for 1 h at 4°C, and subjected to immunoprecipitation in the presence of 0.5% NP-40 with CPEB antibody, APLP1 antibody, or rabbit IgG linked to Dynabead M-280 sheep anti-rabbit IgG (Dynal). The beads were washed in 50 mM Tris, pH 7.5, 1 mM MgCl2, 0.1 mM KCl, 2 mM EDTA, and 0.5% NP-40 and boiled in SDS sample solution.
For some experiments, the APLP1-containing fractions were pooled, diluted fivefold with HB buffer, and centrifuged in Beckman SW41 Ti rotor at 36,000 rpm for 1 h. The pellets were transferred to microcentrifuge tubes and rinsed once with PBS and pelleted at 14,000 rpm for 10 min. The pellets were incubated with CPEB or APLP1 antibody (or IgG as a control) at room temperature for 30 min and then washed with PBS. The pellets were further incubated with 15-nm-diameter gold particle-labeled goat anti-rabbit IgG at room temperature for 30 min, washed with PBS, and then fixed with 2.5% glutaraldehyde.
For other experiments, 50 oocytes were injected with 32P-labeled cyclin B1 3' UTR containing or lacking a CPE. Some oocytes were incubated with progesterone and after germinal vesicle breakdown, they were homogenized and resolved by sucrose gradient centrifugation as above. The RNA from each fraction was then extracted and analyzed by denaturing polyacrylamide gel electrophoresis.
Some oocytes were injected with 15 ng of the RNAs noted above that were labeled with digoxigenin-UTP (dig-11-UTP/UTP ratio = 1:4; Roche). Two hours after injection, the oocytes were collected and subjected to a linear sucrose gradient as above. The membrane-containing fractions, prepared as noted above, were immunostained with 25-nm-diameter gold-labeled sheep anti-digoxigenin IgG. After extensive washing, the membrane pellet was fixed by 2.5% glutaraldehyde.
Transfections.
The RNAs were synthesized with mMessage mMachine and T7 Ultra kits (Ambion) and transfected into 9- to 10-day-old hippocampal neurons. Approximately 17 pmol of myc-CPEB RNA, 6.5 pmol of APLP1, APLP1-ICD, or APLP1-ICD RNA, 1.7 pmol of firefly luciferase RNA appended with a partial 
-CaMKII 3' UTR sequence containing either wild-type or mutated CPEs (42), and 1 pmol of Renilla luciferase RNA were cotransfected via TransMessenger transfection reagent (QIAGEN) for 3 h. Some neurons were then stimulated with 50 µM NMDA for an additional 3 h before lysis in 100 µl of buffer and analysis for dual-luciferase activity (Promega). Luciferase RNAs were quantified by real-time PCR.
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RESULTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Xenopus oocytes, the most efficacious system for examining the biochemistry of polyadenylation (31), were used initially to determine the physiological relevance of the APLP1-CPEB interaction. Oocytes were injected with mRNA encoding full-length APLP1-myc, or APLP1-myc with amino-terminal and carboxy-terminal truncations (cf. Fig. 1A), followed by a second injection of radiolabeled CPE-containing RNA. The oocytes were subsequently treated with a small amount of progesterone (10 ng/ml) that primes the oocytes without stimulating meiotic maturation. While progesterone alone had little effect, APLP1 and APLP1-ICD, but not APLP1-ICD, greatly enhanced polyadenylation (Fig. 2A). APP and APP-ICD, but not APP-ICD, also promoted polyadenylation irrespective of whether the oocytes were incubated with progesterone (Fig. 2B, lanes 3 to 6), although this effect was enhanced by the hormone (lanes 4 and 6). A Western blot indicates that the injected mRNAs were translated to about the same extent (Fig. 2C); the ICDs were too small to detect by this assay.
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ICD, also stimulated maturation when the oocytes were incubated with 10 ng/ml progesterone (Fig. 2D, left). However, when the oocytes were incubated with 100 ng/ml hormone, there was little difference in the rates of maturation irrespective of the agent injected, indicating that the higher steroid dose overrode the APLP1/APP effect (Fig. 2D, right). Finally, mRNAs encoding APLP1, the APLP1-ICD, and APP, but not APLP1-ICD, stimulated translation of a CAT reporter RNA, but only when it contained a CPE (Fig. 2E). These data show that the ICDs of APLP1 and APP stimulate cytoplasmic polyadenylation, CPE-dependent translation, and oocyte maturation.
APLP1 stimulates CPEB S174 phosphorylation.
Cytoplasmic polyadenylation requires Aurora A-catalyzed CPEB serine 174 phosphorylation (threonine 171 in the mouse) (19, 29). To assess whether APLP1 and/or APP might stimulate CPEB phosphorylation, mRNAs encoding these proteins as well as APP-ICD were injected into oocytes, some of which were also incubated with 10 ng/ml progesterone. A Western blot of protein from these oocytes shows that APLP1 induced an electrophoretic mobility shift of CPEB (Fig. 3A, lane 3), which indicates phosphorylation by cdk1, and presumably a preceding Aurora A phosphorylation (29; see below). Soon after this mobility shift, 70 to 80% of the CPEB was destroyed, as noted previously (28). In oocytes from a second frog, both APLP1 and APP, but not these proteins lacking their ICDs, induced a CPEB mobility shift. APLP1-myc interacted with both phosphorylated and nonphosphorylated forms of CPEB since both the fast- and slow-migrating species were coimmunoprecipitated with myc antibody (Fig. 3B, lane 2).
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-32P]ATP and E. coli-expressed wild-type or mutant CPEB containing an S174A substitution followed by SDS-PAGE (Fig. 3C, left). Compared to noninjected controls, CPEB was phosphorylated in extracts only from APLP1-injected oocytes incubated for 4 or 6 h (lanes 1 and 3). The CPEB bands from lanes 1, 2, 5, and 6 were excised, digested with trypsin, and subjected to two-dimensional phosphopeptide mapping. Figure 3C (right) shows that APLP1 stimulated the phosphorylation of a single peptide of CPEB (arrow), which was absent when the S174A mutant CPEB was used as the substrate (panels 1 and 2). Thus, the ICDs of APLP1 and APP bind CPEB and promote Aurora A-catalyzed serine 174 phosphorylation and polyadenylation-induced translation. The cytoplasmic polyadenylation machinery is associated with membranes. Because APP family members span the plasma membrane, we determined whether CPEB and other components of the polyadenylation/translation machinery are also associated with membranes. Immature and progesterone-stimulated oocytes were fractionated on a sucrose gradient to resolve membrane fractions (24), which were then analyzed by Western blots. During maturation, CPEB undergoes two rounds of phosphorylation: the first is Aurora A catalyzed and the second is cdc2 catalyzed. The cdc2 phosphorylations induced a gel mobility shift (29) (Fig. 4A). While CPEB sedimented throughout the gradient, APLP1 was detected only in specific fractions (6-9), which also contained Na/K ATPase, a plasma membrane marker. From these pooled fractions, CPEB and APLP1 were coimmunoprecipitated. To determine whether APLP1 and CPEB were associated with membranes, the fractions were subjected to immunocytochemistry with specific antibodies followed by gold-labeled secondary antibodies and examined by electron microscopy. Both APLP1 and CPEB were found in close proximity with membranes (Fig. 4B). (Because both antibodies were generated in rabbits, double immunogold labeling was not possible.)
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To investigate whether RNA can also be detected in the APLP1-containing fractions, oocytes were injected with CPE-containing and CPE-lacking RNA; some of the oocytes were then treated with progesterone and were fractionated on the sucrose gradients as before. A portion of each fraction was then probed for CPEB and APLP1; RNA was extracted from the remaining portion and was analyzed by denaturing gel electrophoresis. As before, a portion of CPEB cosedimented with APLP1 (Fig. 4D). The RNA, irrespective of whether it contained a CPE, sedimented in a disperse manner throughout the gradient. However, in progesterone-stimulated oocytes, most of the CPE-containing RNA shifted to a denser part of the gradient that contained APLP1; in these fractions, it underwent polyadenylation.
Finally, digoxigenin-labeled CPE-containing and CPE-lacking RNA was injected into oocytes, which were subsequently homogenized and sedimented through sucrose gradients as before, the APLP1-containing fractions were pooled, and the injected RNA was detected by antibody against the digoxigenin moiety and immunogold labeling. While the CPE-containing RNA was detected on membranes, the CPE-lacking RNA was not; it was occasionally associated with an amorphous material (Fig. 4E). The data in Fig. 4 indicate that the polyadenylation machinery, including RNA, is associated with membranes.
Because homogenization and fractionation of cells could induce associations that do not occur in vivo, whole oocytes were fixed and embedded for immunogold detection of proteins. APLP1, Maskin, CPSF100, and Aurora A (the only ones examined) were all found in association with membranes; because the regions shown are directly beneath the plasma membrane, they could represent microvili or recycling endomembranes. (Fig. 5). Thus, at least a portion of these proteins is associated with membranes in vivo.
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ICD, APLP1-ICD, or ß-galactosidase (to equalize the amount of RNA used in each transfection) and firefly luciferase. The last mRNA was appended with a 3' UTR-derived -CaMKII mRNA that contained two CPEs or one in which these CPEs were mutated. Following transfection, one-half of each batch of transfected neurons was treated with NMDA. When expressed as a percentage of change in firefly luciferase activity in neurons transfected with ß-galactosidase, APLP1-ICD had no effect irrespective of whether the firefly luciferase mRNA contained or lacked a CPE (Fig. 6B). However, APLP1 and APLP1-ICD stimulated firefly luciferase activity in a CPE-dependent manner in response to NMDA treatment of neurons (17% for APLP1, P = 0.002, and 15% for APLP1-ICD, P = 0.03; Student's t test). A further quantitative reverse transcription-PCR analysis of the firefly and Renilla luciferase mRNAs showed that they were equally stable irrespective of whether ß-galactosidase, APLP1, APLP1-ICD, or APLP1-ICD was cotransfected into untreated or NMDA-treated neurons (Fig. 6B). These data demonstrate that the ICD of APLP1 enhances CPE-dependent mRNA translation in neurons.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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APP and APLP are found not only on the plasma membrane, but also on the endoplasmic reticulum, Golgi apparatus, and endomembranes as they cycle to lysosomes (40). Although CPEB, CPSF, etc., cosediment with Na/K ATPase, a plasma membrane marker, and appear to be associated with plasma membranes as assessed by immunoelectron microscopy, they may be associated with these other membranes as well. The localization of CPE-containing RNA on the membranes is almost certainly due to the CPEB-APLP1 complex and not the RNA per se. That is, mRNAs encoding secreted proteins associate with the endoplasmic reticulum through interactions between the signal peptide and the signal recognition particle (16). The digoxigenin-labeled RNA we injected contained no open reading frame; thus, no nascent peptide could be involved in localizing the RNA.
Why is the polyadenylation/translation machinery localized to membranes? In oocytes, progesterone stimulates M-phase progression not by activating transcription but by stimulating a membrane-associated receptor, possibly a G-protein-coupled receptor (44; but see also reference 26). If APLP1 helps concentrate CPEB and the other factors near the progesterone receptor, a wave of polyadenylation/translation could begin locally and then subsequently spread throughout the oocyte. This possibility seems attractive given the huge volume of these cells (1 µl); an immediate and local response to progesterone stimulation could facilitate meiotic progression.
Groisman et al. (15) immunostained oocytes for CPEB and Maskin and found that although these two factors were present throughout the cytoplasm, they were somewhat concentrated in the cortex of the animal pole. At the electron microscope level, the present study also found these factors to be present throughout the oocyte, but also in cortical regions that contain membranes. After fertilization, much of the CPEB that is present in the vegetal region is destroyed and at least some of that which remains stable becomes associated with spindles and centrosomes of the early embryo that are formed in the animal pole cytoplasm (15). Not only is CPEB found on spindles and centrosomes, but Maskin, CPSF, and eIF4E are as well. While we have no evidence that the membrane-associated CPEB, Maskin, CPSF, etc., in oocytes subsequently become associated with the mitotic apparatus in embryos after fertilization, it is tempting to speculate that this could be the case. Irrespective of this possibility, these data do show a remarkable and differential localization of the polyadenylation/translation machinery in early development.
In the brain, APP undergoes a series of proteolytic cleavages by the -, ß-, and -secretase/presenilin system to produce not only the extracellular neurofibrillary tangles thought to be causative for Alzheimer's disease but also the liberation of the ICDs that, among other activities, stimulate transcription (8). We do not know whether oocytes contain active -secretase activity: we have been unable to detect free (cleaved) APLP1 (our antibody against mammalian APP can detect no clear immunoreactivity in Xenopus cells). On the other hand, the ICD of APLP1 is small, 5 kDa, and thus would probably not be readily observed by Western blotting. However, the ICD has about the same polyadenylation-stimulating activity as the uncleaved membrane-bound APLP1. This result might seem surprising since the ICD presumably would not be localized with the polyadenylation machinery. On the other hand, such a peptide would probably diffuse rather freely and, once in contact with an Aurora A/CPEB complex, could stimulate CPEB S174 phoshorylation and resulting polyadenylation. How the ICD stimulates this event is unclear; it does not enhance CPEB phosphorylation when mixed with recombinant CPEB and Aurora A in vitro (data not shown).
In neurons, CPEB-mediated polyadenylation/translation is regulated via NMDARs (22, 42), which are calcium ion channels. NMDA induces CPEB phosphorylation by Aurora A (22) and perhaps -CaMKII as well (4). However, calcium probably does not activate Aurora A directly but may modify other upstream effectors such as those that signal to GSK3ß, one of several factors that control Aurora A activity in oocytes (34) and, because it modifies synaptic plasticity, possibly neurons as well (14). APP, like CPEB, is detected in dendrites and in postsynaptic densities (36, 37) and modulates synaptic plasticity (40). We surmise that the function of the APLP1-CPEB complex in neurons, like that in oocytes, is to promote rapid local polyadenylation and translation. Indeed, neurons and oocytes seem remarkably similar in the basic molecular mechanism that regulates polyadenylation and translation (33).
Gene knockouts of the APP family members, both singly and in combination, have demonstrated at least partially redundant functions of the proteins (17). For example, while single APP family gene knockouts have relatively mild phenotypes (e.g., APP–/–) (43), double knockouts (e.g., APP–/–/APLP2–/– and APLP1–/–/APLP2–/–) are lethal (17). While it is not known whether the ICDs of these proteins are the portions responsible for this redundancy in animals, the fact that they are structurally similar suggests that they might contribute to it. This redundancy makes it somewhat difficult to determine whether all or some of the proteins contribute to CPEB-mediated translation in neurons. Nonetheless, future experiments will be directed toward addressing this issue.
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ACKNOWLEDGMENTS |
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This work was supported by grants from the NIH. Core support from the Diabetes Endocrinology Research Center Program Project (DK32520) is also gratefully acknowledged.
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FOOTNOTES |
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