CPEB4
CPEB4 – cytoplasmic polyadenylation element binding protein 4 is RNA-binding protein, which is an exemplary key post-transcriptional regulator and is of paramount importance for fine-tuning protein synthesis and pathological cellular phenotypes. It belongs to CPEB-like proteins which are composed of four paralogs (CPEB1~4), and many studies have elucidated the biological functions of CPEB1 and CPEB4 in health and disease.[1] Similar to the other CPEBs, CPEB4 is known to associate via its two conserved tandem RNA recognition motifs (RRMs) with the cytoplasmic polyadenylation element (CPE), a U-rich and A-rich motif located in the 3′UTR of specific mRNAs. CPEB4 is known to maintain poly(A) tail length and to enhance the translation of individual mRNAs by assemble an activator complex promoting the translation of target mRNAs through cytoplasmic polyadenylation.[2]
CPEB4 is specifically induced during erythroid differentiation and attributed repression and activation roles regarding cytoplasmic polyadenylation.[3]
CPEB4 Is also functionally linked with the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme (PFKFB3) during hepatic stellate cell (HSC) activation. CPEB4 protein is up-regulated early during HSC activation and binds directly to CPE elements present on the 3'-untranslated region of the PFKFB3 transcript. This favors PFKFB3 mRNA cytoplasmic polyadenylation and, in turn, activates translation and generates high levels of the glycolysis activator PFKFB3. Silencing CPEB4 prevents the up-regulation of PFKFB3 observed in pathological conditions, but does not completely abrogate PFKFB3 protein expression, which is necessary to maintain cellular homeostasis, suggesting the possible benefit of using CPEB4 inhibitors. So, targeting CPEB4 may be efficacious in treating liver fibrosis to counteract fibrosis progression by obstructing the metabolic evolution of activated HSCs without causing damage to healthy cells.[4]
Both CPEB1 and CPEB4 are involved in tissue repair or fibrotic scarring. CPEB1 and CPEB4 were upregulated on day 2 (inflammatory stage) and day 5 (proliferative stage) in the process of wound healing.[5] In an LPS-induced sepsis model, depletion of CPEB4 in mouse macrophages impaired resolution of inflammation as the result of a regulatory imbalance where "RNA-binding proteins CPEB4 (cytoplasmic polyadenylation element binding protein 4) and TTP (tristetraprolin) act oppositely to regulate RNA stability in macrophages and modulate inflammation".[6]
CPEB4 is downregulated during aging in various tissues, and loss of CPEB4 impairs senescenct cellular functions in adult mice[7]
References
- ↑ Fernández-Miranda, G., & Méndez, R. (2012). The CPEB-family of proteins, translational control in senescence and cancer. Ageing research reviews, 11(4), 460-472. PMID: 22542725 DOI: 10.1016/j.arr.2012.03.004
- ↑ Schelhorn, C., Gordon, J. M., Ruiz, L., Alguacil, J., Pedroso, E., & Macias, M. J. (2014). RNA recognition and self-association of CPEB4 is mediated by its tandem RRM domains. Nucleic acids research, 42(15), 10185-10195. PMID: 25081215 PMCID: PMC4150798 DOI: 10.1093/nar/gku700
- ↑ Hu, W., Yuan, B., & Lodish, H. F. (2014). Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation. Developmental cell, 30(6), 660-672. PMID: 25220394 PMCID: PMC4182162 DOI: 10.1016/j.devcel.2014.07.008
- ↑ Mejias, M., Gallego, J., Naranjo-Suarez, S., Ramirez, M., Pell, N., Manzano, A., ... & Fernandez, M. (2020). CPEB4 increases expression of PFKFB3 to induce glycolysis and activate mouse and human hepatic stellate cells, promoting liver fibrosis. Gastroenterology, 159(1), 273-288. PMID: 32169429 DOI: 10.1053/j.gastro.2020.03.008
- ↑ Cui, H. S., Lee, Y. R., Ro, Y. M., Joo, S. Y., Cho, Y. S., Kim, J. B., ... & Seo, C. H. (2023). Knockdown of CPEB1 and CPEB4 Inhibits Scar Formation via Modulation of TAK1 and SMAD Signaling. Annals of Dermatology, 35(4), 293. PMID: 37550230 PMCID: PMC10407338 DOI: 10.5021/ad.22.210
- ↑ Suñer, C., Sibilio, A., Martín, J., Castellazzi, C. L., Reina, O., Dotu, I., ... & Méndez, R. (2022). Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation. Elife, 11, e75873. PMID: 35442882 PMCID: PMC9094754 DOI: 10.7554/eLife.75873
- ↑ Zeng, W., Zhang, W., Erin, H. Y., Liu, J., Dong, A., Lam, K. S., ... & Cheung, T. H. (2023). Restoration of CPEB4 prevents muscle stem cell senescence during aging. Developmental Cell. PMID: 37321216 DOI: 10.1016/j.devcel.2023.05.012
