Subsequently, Cdk1 and Polo-like kinase 1 (Plk1) target CPEB1 NTD to ubiquitin-mediated degradation. First, Aurora kinase A (AurKA) phosphorylates CPEB1 at S174, promoting the switch from a repressor to an activator. Specifically, CPEB1 is regulated by two sequential phosphorylation events. For CPEB1 and CPEB4, the switch from repression to activation is differentially regulated through post-translational modifications in the NTD. The CPEB N-terminal domain (NTD) is highly variable both in length and composition across various CPEB orthologs and paralogs and contains intrinsically disordered regions (IDR), which are more extended in CPEB2–4 (Additional file 1: Fig. However, the structures of these regions, both in the free state and bound to a CPE, revealed that recognition of the CPE by CPEBs is different between CPEB1 and CPEB2-4. CPEBs share similar C-terminal RNA-binding domains, comprising two RNA recognition motifs (RRMs) in tandem, followed by a ZZ domain (a zinc-binding domain with a cross-braced zinc binding topology). S1B), potentially co-regulating overlapping populations of transcripts. Thus, multiple CPEBs co-exist in individual cells (Additional file 1: Fig. All four vertebrate CPEBs are differentially expressed in somatic tissues but with overlapping patterns. The “primitive” CPEB appears to be CPEB1/ApCPEB/Orb, whereas CPEB2–4 are more similar between themselves and to Orb2. ![]() Thus, Aplysia has only one CPEB (ApCPEB), Drosophila has two (Orb and Orb2), and all vertebrates have four (CPEB1–4). This family of proteins appears to have evolved by gene duplication and divergence (Additional file 1: Fig. In turn, CPEBs regulate mRNA translation, either by assembling repressor complexes that maintain target transcripts translationally silenced or by promoting cytoplasmic polyadenylation and subsequent translational activation. These cis-acting elements recruit members of the CPE-binding protein (CPEB) family of RNA-binding proteins. ConclusionsĪltogether, these results show how, globally, the CPEB family of proteins is able to integrate cellular cues to generate a fine-tuned adaptive response in gene expression regulation through the coordinated actions of all four members.Īn estimated 20–30% of all vertebrate genes are regulated by the cytoplasmic polyadenylation elements (CPEs) that are present in the 3′ UTR of their transcripts. CPEB2–4 mRNA targets include CPEB1-bound transcripts, with canonical CPEs, but also a specific subset of mRNAs with non-canonical CPEs. CPEB2–4 are regulated by multiple proline-directed phosphorylations that control their liquid–liquid phase separation. ![]() Thus, CPEB1 forms ribonucleoprotein complexes that are remodeled upon a single phosphorylation event and are associated with mRNAs containing canonical CPEs. However, their regulation, mechanism of action, and target mRNAs define two subfamilies. We show that all four CPEBs are able to recruit the CCR4-NOT deadenylation complex to repress the translation. Resultsīased on a comparative analysis of the four vertebrate CPEBs, we determine their differential regulation by phosphorylation, the composition and properties of their supramolecular assemblies, and their target mRNAs. However, neither the regulation nor the mechanisms of action of the CPEB family per se have been systematically addressed to date. Vertebrate CPEB proteins bind mRNAs at cytoplasmic polyadenylation elements (CPEs) in their 3′ UTRs, leading to cytoplasmic changes in their poly(A) tail lengths this can promote translational repression or activation of the mRNA.
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