View source for CPEB

{{Short description|Protein}}
{{For|the 18th century German composer|Carl Philipp Emanuel Bach}}
{{Infobox protein family|Symbol=CPEB|Name=Cytoplasmic polyadenylation element binding protein|image=CPEB Proteins.jpg|caption=Properties of CPEBs and their interactions with other proteins in RNP complexes|InterPro=IPR034819|Pfam=PF16366|Pfam_clan=|class=mw-collapsible mw-collapsed}}'''CPEB''', or '''[[cytoplasmic polyadenylation element]] binding protein''', is a highly [[Conserved sequence|conserved]] [[RNA]]-binding [[protein]] that promotes the elongation of the [[polyadenylation|polyadenine tail]] of [[messenger RNA]].<ref name = "Kim_2010">{{cite book | vauthors = Kim JH, Richter JD | chapter = Chapter 278 - Signaling to Cytoplasmic Polyadenylation and Translation |date= January 2010 | title = Handbook of Cell Signaling | edition = Second |pages=2317–2321 | veditors = Bradshaw RA, Dennis EA |place=San Diego |publisher=Academic Press |doi=10.1016/b978-0-12-374145-5.00278-3 |isbn=978-0-12-374145-5 }}</ref> CPEB is present at postsynaptic sites and dendrites where it stimulates polyadenylation and translation in response to synaptic activity.<ref name="Hake_1994">{{cite journal | vauthors = Hake LE, Richter JD | title = CPEB is a specificity factor that mediates cytoplasmic polyadenylation during Xenopus oocyte maturation | journal = Cell | volume = 79 | issue = 4 | pages = 617–627 | date = November 1994 | pmid = 7954828 | doi = 10.1016/0092-8674(94)90547-9 | s2cid = 42910508 }}</ref> CPEB most commonly activates the target RNA for [[translation (genetics)|translation]], but can also act as a repressor,<ref name="de Moor">{{cite journal | vauthors = de Moor CH, Richter JD | title = Cytoplasmic polyadenylation elements mediate masking and unmasking of cyclin B1 mRNA | journal = The EMBO Journal | volume = 18 | issue = 8 | pages = 2294–2303 | date = April 1999 | pmid = 10205182 | pmc = 1171312 | doi = 10.1093/emboj/18.8.2294 }}</ref> dependent on its [[phosphorylation]] state.<ref name="Mendez">{{cite journal | vauthors = Mendez R, Barnard D, Richter JD | title = Differential mRNA translation and meiotic progression require Cdc2-mediated CPEB destruction | journal = The EMBO Journal | volume = 21 | issue = 7 | pages = 1833–1844 | date = April 2002 | pmid = 11927567 | pmc = 125948 | doi = 10.1093/emboj/21.7.1833 }}</ref> As a repressor, CPEB interacts with the deadenylation complex and shortens the polyadenine tail of mRNAs.<ref name = "Kozlov_2021">{{cite journal | vauthors = Kozlov E, Shidlovskii YV, Gilmutdinov R, Schedl P, Zhukova M | title = The role of CPEB family proteins in the nervous system function in the norm and pathology | journal = Cell & Bioscience | volume = 11 | issue = 1 | pages = 64 | date = March 2021 | pmid = 33789753 | pmc = 8011179 | doi = 10.1186/s13578-021-00577-6 | doi-access = free }}</ref> In animals, CPEB is expressed in several [[alternative splicing]] isoforms that are specific to particular tissues and functions, including the self-cleaving [[Mammalian CPEB3 ribozyme]]. CPEB was first identified in ''[[Xenopus]]'' [[oocyte]]s and associated with [[meiosis]];<ref name="Hake_1994" /> a role has also been identified in the [[spermatogenesis]] of ''[[Caenorhabditis elegans]]''.<ref name="Luitjens">{{cite journal | vauthors = Luitjens C, Gallegos M, Kraemer B, Kimble J, Wickens M | title = CPEB proteins control two key steps in spermatogenesis in C. elegans | journal = Genes & Development | volume = 14 | issue = 20 | pages = 2596–2609 | date = October 2000 | pmid = 11040214 | pmc = 316992 | doi = 10.1101/gad.831700 }}</ref>
CPEB is involved in closed-loop regulation of mRNAs that keeps them inactive. The closed-loop structure between the [[3'UTR]] and [[5'UTR]] inhibits translation.<ref name="Kang 2011 147–157">{{cite journal | vauthors = Kang MK, Han SJ | title = Post-transcriptional and post-translational regulation during mouse oocyte maturation | journal = BMB Reports | volume = 44 | issue = 3 | pages = 147–157 | date = March 2011 | pmid = 21429291 | doi = 10.5483/BMBRep.2011.44.3.147 | series = 3 | doi-access = free }}</ref>  This has been observed in ''[[Xenopus laevis]]'' in which [[eIF4E]] bound to the [[5' cap]] interacts with Maskin bound to CPEB on the [[3' UTR]] creating translationally inactive [[mRNA|transcripts]]. This translational inhibition is lifted once CPEB is [[phosphorylated]], displacing the Maskin binding site, allowing for the [[polymerization]] of the [[PolyA tail]], which can recruit the translational machinery by means of [[PolyA-binding protein|PABP]].<ref>{{cite book| vauthors = Gilbert S |title=Developmental Biology|url=https://archive.org/details/developmentalbio00gilb_892|url-access=limited|year=2010|publisher=Sinauer Associates, Inc.|location=Sunderland, MA|isbn=978-0-87893-384-6|page=[https://archive.org/details/developmentalbio00gilb_892/page/n84 60]}}</ref> However, <ref name="Lin_2010">{{cite journal | vauthors = Lin CL, Evans V, Shen S, Xing Y, Richter JD | title = The nuclear experience of CPEB: implications for RNA processing and translational control | journal = RNA | volume = 16 | issue = 2 | pages = 338–348 | date = February 2010 | pmid = 20040591 | pmc = 2811663 | doi = 10.1261/rna.1779810 }}</ref> is important to note that this mechanism has been under great scrutiny.<ref>{{cite journal | vauthors = Kozak M | title = Faulty old ideas about translational regulation paved the way for current confusion about how microRNAs function | journal = Gene | volume = 423 | issue = 2 | pages = 108–115 | date = November 2008 | pmid = 18692553 | doi = 10.1016/j.gene.2008.07.013 | series = 2 }}</ref>
CPEB has been shown to shuttle between the nucleus and [[cytoplasm]].<ref name="Lin_2010" /> In the nuclei of different organisms, it was found that CPEB helps guide the path of mRNA in the cytoplasm.<ref name="Hake_1994" />  CPEB was found to be almost exclusively in the c<ref name="Lin_2010" /> plasm in stage VI ''Xenopus'' oocytes.<ref name="Hake_1994" /> However, a further study on this topic found that there is a substantial amount of CPEB in the nucleus.<ref name="Lin_2010" /> CPEB can bind with CPE-containing mRNAs in the nucleus, which forces tight [[translational regulation]] in the cytoplasm. CPEBs bound to these mRNAs were found to have <ref name="Giangarrà_2015">{{cite journal | vauthors = Giangarrà V, Igea A, Castellazzi CL, Bava FA, Mendez R | title = Global Analysis of CPEBs Reveals Sequential and Non-Redundant Functions in Mitotic Cell Cycle | journal = PLOS ONE | volume = 10 | issue = 9 | pages = e0138794 | date = 2015-09-23 | pmid = 26398195 | pmc = 4580432 | doi = 10.1371/journal.pone.0138794 | bibcode = 2015PLoSO..1038794G | veditors = Jan E | doi-access = free }}</ref>wer translation efficiency, which is indicative of the translation regulation.
== Protein Family ==
CPEB can also refer to the family of proteins.<ref name="Giangarrà_2015" /> There are four proteins in the protein family:
* '''[[CPEB1]]'''
* '''CPEB2'''
* '''CPEB3'''
* '''CPEB4'''
This protein family can be divided into two subfamilies. The groups are separated by their<ref name="Duran-Arqué_2022">{{cite journal | vauthors = Duran-Arqué B, Cañete M, Castellazzi CL, Bartomeu A, Ferrer-Caelles A, Reina O, Caballé A, Gay M, Arauz-Garofalo G, Belloc E, Mendez R | display-authors = 6 | title = Comparative analyses of vertebrate CPEB proteins define two subfamilies with coordinated yet distinct functions in post-transcriptional gene regulation | journal = Genome Biology | volume = 23 | issue = 1 | pages = 192 | date = September 2022 | pmid = 36096799 | doi = 10.1186/s13059-022-02759-y | pmc = 9465852 | doi-access = free }}</ref> ..specific properties in target/motif recognition, large-order complex co-factors, and dynamic properties and regulation during cell cycle."<ref name="Duran-Arqué_2022" /> The first subfamily contains only CPEB1 and the second contains CPEB2 - CPEB4. The general CPE that CPEBs bind to has a canonical UUUUAU sequence, which all four of the proteins can recognize. However, CPEB1 can only recognize CPEs with the canonical sequence, while the second group of CPEB2–4 can also bind to variants of the CPE, known as G-variants due to their sequence difference (UUUUGU). This suggests that CPEB2–4 has other targets that it can hit in addition to CPEB1 targets.
== Structure ==
The CPEB structure consists of "...an [[amino-terminal]] port<ref name="Hake_1998">{{cite journal | vauthors = Hake LE, Mendez R, Richter JD | title = Specificity of RNA binding by CPEB: requirement for RNA recognition motifs and a novel zinc finger | journal = Molecular and Cellular Biology | volume = 18 | issue = 2 | pages = 685–693 | date = February 1998 | pmid = 9447964 | pmc = 108779 | doi = 10.1128/MCB.18.2.685 }}</ref>  with no obvious functional motif, two [[RNA recognition motif|RNA recognition motifs]] (RRMS), and a cysteine-histidine region that is reminiscent of a zinc finger."<ref name="Hake_1998" /> The zinc finger region and RRMs are necessary for RNA bind.<ref name="Hake_1998" /> It was found that CPEB bound to other metals than zinc destroyed RNA binding, but the binding would be restored if supplemented with zinc.<ref name="Hake_1998" /> Proteins lacking any of the RRMs were also shown to be less efficient in binding RNA.
Not all of the regions are the same across the different forms of CPEB. The amino terminus can differ substantially across the proteins. The prion-like isoform of CPEB found in ''Aplysia californica, Drosophila,'' mice, and humans is an example of such differentiation.<ref name = "Kozlov_2021" /> This isoform is prion-like due to the presence of polyglutamine- or polyalanine-rich domains at the N-terminus.<ref name = "Kozlov_2021" />
== Neurological disorders ==
A misstep in the process of translation with CPEB can lead to possible adverse affects on neurological development. Risk genes for [[Autism spectrum|autism spectrum disorder]] were found in brains where "...CPEB4 transcript isoform imbalance due to decreased inclusion of a neuronal-specific microexon together with a new molecular signature of global polyadenine tail shortening..."<ref>{{cite journal | vauthors = Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A, Nieto-González JL, Picó S, Hernández IH, Díaz-Hernández JI, Belloc E, Rodolosse A, Parikshak NN, Peñagarikano O, Fernández-Chacón R, Irimia M, Navarro P, Geschwind DH, Méndez R, Lucas JJ | display-authors = 6 | title = Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing | journal = Nature | volume = 560 | issue = 7719 | pages = 441–446 | date = August 2018 | pmid = 30111840 | pmc = 6217926 | doi = 10.1038/s41586-018-0423-5 | bibcode = 2018Natur.560..441P }}</ref> In idiopathic autism spectrum disorder individuals, CPEB4 is greatly decreased and showed significant splicing alterations. An equivalent isoform imbalance in mice mimics changes of autism spectrum disorder genes, which causes similar neuroanatomical, electrophysiological, and behavioral phenotype expression.
Gene regulation of CPEB proteins is also proposed as a target for gene therapy..<ref name = "Kozlov_2021" /> [[Fragile X syndrome]] and [[Huntington's disease]] are two such disorders and diseases where CPEB regulation has been used to attempt recovery of brain function. There is not a cure for either of these afflictions, but translation dysfunction of CPEB proteins can be a cause for either.<ref name="Joag_2020">{{cite journal | vauthors = Joag H, Ghatpande V, Desai M, Sarkar M, Raina A, Shinde M, Chitale R, Deo A, Bose T, Majumdar A | display-authors = 6 | title = A role of cellular translation regulation associated with toxic Huntingtin protein | journal = Cellular and Molecular Life Sciences | volume = 77 | issue = 18 | pages = 3657–3670 | date = September 2020 | pmid = 31796991 | doi = 10.1007/s00018-019-03392-y | s2cid = 198249367 | pmc = 11105026 }}</ref> When modeling fragile X syndrome in mice, CPEB1 gene mutations reduced pathological processes associated with the disorder.<ref>{{cite journal | vauthors = Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD | display-authors = 6 | title = Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology | journal = Nature Medicine | volume = 19 | issue = 11 | pages = 1473–1477 | date = November 2013 | pmid = 24141422 | pmc = 3823751 | doi = 10.1038/nm.3353 }}</ref> A decrease in CPEB1 restored the balance of mRNA translation, which can be achieved by manipulating levels of miRNAs.
For Huntington's disease, a study on a ''Drosophila'' cell culture showed that the ''Drosophila'' Orb2A protein was absorbed on the surface of [[Huntingtin|Huntingtin gene (Htt)]] aggregates''.''<ref name="Joag_2020" /> The aggregates lead to a protein synthesis imbalance, cell decay, and neuron death. The absorption of the protein caused a partial reduction of the lethality of the Htt aggregates. The aggregates did not decrease, but protein synthesis balance was restored in the cells. However, CPEB sequestration translation dysfunction is not a definite cause of Huntington's disease symptoms in humans. Other RNA binding proteins could be other possible targets for translation dysfunction in patients with this disease.
== Role in cellular senescence ==
CPEB has been found to help regulate [[cellular senescence]] through modulating [[p53]] mRNA polyadenylation-induced translation.<ref name="Burns_2008">{{cite journal | vauthors = Burns DM, Richter JD | title = CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation | journal = Genes & Development | volume = 22 | issue = 24 | pages = 3449–3460 | date = December 2008 | pmid = 19141477 | pmc = 2607074 | doi = 10.1101/gad.1697808 }}</ref> When human skin and lung cells were put under a knockdown of CPEB, they bypassed the M1 crisis stage of senescence. This bypass is required for cellular transformation. Reduced CPEB levels also affected the rate at which cell division occurred, slowing down the process until the cells ceased to divide. In mice, reduced CPEB levels caused cells to become immortal.<ref name="Burns_2008" /> A senescence-like phenotype recurred when CPEB was introduced into early passage cells, but not late passage cells. Senescence is considered an irreversible process, but the CPEB-induced senescence-like phenotype can possibly refute that. CPEB is thus shown to regulate senescence, as well as mediate immortalization in cells.
==Role in memory==
Drosophila Orb2 binds to genes implicated in long-term memory. An isoform of CPEB found in the [[neuron]]s of the sea slug ''[[Aplysia californica]]'', as well as in ''[[Drosophila]]'', mice, and humans, contains an [[N-terminus|N-terminal]] domain not found in other isoforms that shows high sequence similarity to [[prion]] proteins. Experiments with the ''Aplysia'' isoform expressed in [[yeast]] reveal that CPEB has a key property associated with prions: it can cause other proteins to assume alternate [[tertiary structure|protein conformations]] that are [[heritable]] in successive generations of yeast cells. Furthermore, the functional RNA-binding form of the CPEB protein may be the prion-like state.<ref name="Si">{{cite journal | vauthors = Si K, Lindquist S, Kandel ER | title = A neuronal isoform of the aplysia CPEB has prion-like properties | journal = Cell | volume = 115 | issue = 7 | pages = 879–891 | date = December 2003 | pmid = 14697205 | doi = 10.1016/s0092-8674(03)01020-1 | doi-access = free }}</ref> These observations have led to the suggestion that long-lasting bistable prionlike proteins play a role in the formation of long-term [[memory]].<ref name="Shorter">{{cite journal | vauthors = Shorter J, Lindquist S | title = Prions as adaptive conduits of memory and inheritance | journal = Nature Reviews. Genetics | volume = 6 | issue = 6 | pages = 435–450 | date = June 2005 | pmid = 15931169 | doi = 10.1038/nrg1616 | s2cid = 5575951 }}</ref>
It has been suggested that "both memory storage and its underlying synaptic plasticity are mediated by the increase in. . .CPEB."<ref name="pmid26074003">{{cite journal | vauthors = Fioriti L, Myers C, Huang YY, Li X, Stephan JS, Trifilieff P, Colnaghi L, Kosmidis S, Drisaldi B, Pavlopoulos E, Kandel ER | title = The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3 | journal = Neuron | volume = 86 | issue = 6 | pages = 1433–48 | date = June 2015 | pmid = 26074003 | doi = 10.1016/j.neuron.2015.05.021 | s2cid = 6196083 | doi-access = free }}</ref>
== Role in oogenesis and embryonic development ==
CPEBs are responsible for the polyadenine tail length in oocytes during [[oogenesis]]. In ''Xenopus'' and mice oocytes, CPEB has been noted to control oocyte growth. Regulation of follicle development has been noted specifically in mice.<ref>{{cite journal | vauthors = Conti M, Franciosi F | title = Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events | journal = Human Reproduction Update | volume = 24 | issue = 3 | pages = 245–266 | date = May 2018 | pmid = 29432538 | pmc = 5907346 | doi = 10.1093/humupd/dmx040 }}</ref> CPEB regulates oocyte development and follicle development in the [[dictyate]] stage through phosphorylation and dephosphorylation.<ref name="Racki_2006">{{cite journal | vauthors = Racki WJ, Richter JD | title = CPEB controls oocyte growth and follicle development in the mouse | journal = Development | volume = 133 | issue = 22 | pages = 4527–4537 | date = November 2006 | pmid = 17050619 | doi = 10.1242/dev.02651 | s2cid = 14891558 | doi-access = free }}</ref> During pachytene, CPEB is phosphorylated, which controls polyadenylation and translation of mRNAs.<ref name = "Kim_2010" /> An experiment was conducted to determine how CPEB affected development by inhibiting the protein in mice. It was found that CPEB regulates [[Growth differentiation factor-9|Gdf9]], a growth factor necessary for follicle development. Without CPEB, Gdf9 had a shortened polyadenine tail and reduced expression. It was also found that progressive oocyte loss and infertility arose from the knockdown of CPEB in oocytes, which resembles premature ovarian failure syndrome in humans.<ref name="Racki_2006" />
== Interactions ==
CPEB has been shown to [[Protein-protein interaction|interact]] with the following proteins:
* [[PUM2]]<ref name ="Campbell_2012">{{cite journal | vauthors = Campbell ZT, Menichelli E, Friend K, Wu J, Kimble J, Williamson JR, Wickens M | title = Identification of a conserved interface between PUF and CPEB proteins | journal = The Journal of Biological Chemistry | volume = 287 | issue = 22 | pages = 18854–18862 | date = May 2012 | pmid = 22496444 | pmc = 3365739 | doi = 10.1074/jbc.M112.352815 | doi-access = free }}</ref>
* [[PARN]]<ref name="Lin_2010" />
* [[GLD-2]]<ref name="Lin_2010" />
* [[SYMPK|symplekin]]<ref name ="Campbell_2012" />
* [[EIF4EBP1|eIF4E binding protein]]<ref name="Lin_2010" />
== References ==
{{reflist}}
[[Category:RNA-binding proteins]]
[[Category:Neuroscience of memory]]
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