BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

EBP1 regulates Suv39H1 stability via the ubiquitin-proteasome system in neural development

  • Kim, Byeong-Seong (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Ko, Hyo Rim (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Hwang, Inwoo (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Cho, Sung-Woo (Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine) ;
  • Ahn, Jee-Yin (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine)
  • Received : 2021.02.16
  • Accepted : 2021.03.08
  • Published : 2021.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

ErbB3-binding protein 1 (EBP1) is a multifunctional protein associated with neural development. Loss of Ebp1 leads to upregulation of the gene silencing unit suppressor of variegation 3-9 homolog 1 (Suv39H1)/DNA (cytosine 5)-methyltransferase (DNMT1). EBP1 directly binds to the promoter region of DNMT1, repressing DNA methylation, and hence, promoting neural development. In the current study, we showed that EBP1 suppresses histone methyltransferase activity of Suv39H1 by promoting ubiquitin-proteasome system (UPS)-dependent degradation of Suv39H1. In addition, we showed that EBP1 directly interacts with Suv39H1, and this interaction is required for recruiting the E3 ligase MDM2 for Suv39H1 degradation. Thus, our findings suggest that EBP1 regulates UPS-dependent degradation of Suv39H1 to govern proper heterochromatin assembly during neural development.

Keywords

Acknowledgement

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government [Ministry of Science, Information and Communication Technology and Future Planning (MSIP)] (2016R1A5A2945889 and 2020R1A2C2003268).

References

  1. Yoo JY, Wang XW, Rishi AK et al (2000) Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin. Brit J Cancer 82, 683-690 https://doi.org/10.1054/bjoc.1999.0981
  2. Liu Z, Ahn JY, Liu X and Ye K (2006) Ebp1 isoforms distinctively regulate cell survival and differentiation. Proc Natl Acad Sci U S A 103, 10917-10922 https://doi.org/10.1073/pnas.0602923103
  3. Ahn JY, Liu X, Liu Z et al (2006) Nuclear Akt associates with PKC-phosphorylated Ebp1, preventing DNA fragmentation by inhibition of caspase-activated DNase. EMBO J 25, 2083-2095 https://doi.org/10.1038/sj.emboj.7601111
  4. Kim CK, Nguyen TLX, Joo KM et al (2010) Negative regulation of p53 by the long isoform of ErbB3 binding protein Ebp1 in brain tumors. Cancer Res 70, 9730-9741 https://doi.org/10.1158/0008-5472.CAN-10-1882
  5. Ko HR, Kim CK, Lee SB et al (2014) P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP. Cell Death Dis 5, e1131-e1131 https://doi.org/10.1038/cddis.2014.79
  6. Hwang I and Ahn JY (2020) Dysregulation of epigenetic control contributes to Schizophrenia-like behavior in Ebp1+/- mice. Int J Mol Sci 21, 2609 https://doi.org/10.3390/ijms21072609
  7. Ko HR, Hwang I, Ahn SY, Chang YS, Park WS, and Ahn JY (2017) Neuron-specific expression of p48 Ebp1 during murine brain development and its contribution to CNS axon regeneration. BMB Rep 50, 126-131 https://doi.org/10.5483/BMBRep.2017.50.3.190
  8. Ko HR, Hwang I, Jin EJ et al (2019) Roles of ErbB3-binding protein 1 (EBP1) in embryonic development and gene-silencing control. Proc Natl Acad Sci U S A 116, 24852-24860 https://doi.org/10.1073/pnas.1916306116
  9. Kim CK, Lee SB, Nguyen TLX et al (2012) Long isoform of ErbB3 binding protein, p48, mediates protein kinase B/Akt-dependent HDM2 stabilization and nuclear localization. Exp Cell Res 318, 136-143 https://doi.org/10.1016/j.yexcr.2011.08.013
  10. Boros J, Arnoult N, Stroobant V, Collet JF and Decottignies A (2014) Polycomb repressive complex 2 and H3K27me3 cooperate with H3K9 methylation to maintain heterochromatin protein 1α at chromatin. Mol Cell Biol 34, 3662-3674 https://doi.org/10.1128/MCB.00205-14
  11. Towbin BD, Gonzalez-Aguilera C, Sack R et al (2012) Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150, 934-947 https://doi.org/10.1016/j.cell.2012.06.051
  12. Bosch-Presegue L, Raurell-Vila H, Marazuela-Duque A et al (2011) Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol Cell 42, 210-223 https://doi.org/10.1016/j.molcel.2011.02.034
  13. Marine JC and Lozano G (2010) Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 17, 93-102 https://doi.org/10.1038/cdd.2009.68
  14. Chen L, Li Z, Zwolinska AK et al (2010) MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output. EMBO J 29, 2538-2552 https://doi.org/10.1038/emboj.2010.140
  15. Dambacher S, Hahn M and Schotta G (2010) Epigenetic regulation of development by histone lysine methylation. Heredity 105, 24-37 https://doi.org/10.1038/hdy.2010.49
  16. Peters AHFM, O'Carroll D, Scherthan H et al (2001) Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323-337 https://doi.org/10.1016/S0092-8674(01)00542-6
  17. Nguyen LXT, Zhu L, Lee Y, Ta L and Mitchell BS (2016) Expression and role of the ErbB3-binding protein 1 in acute myelogenous leukemic cells. Clin Cancer Res 22, 3320-3327 https://doi.org/10.1158/1078-0432.CCR-15-2282
  18. Ko HR, Chang YS, Park WS and Ahn JY (2016) Opposing roles of the two isoforms of ErbB3 binding protein 1 in human cancer cells. Int J Cancer 139, 1202-1208 https://doi.org/10.1002/ijc.30165
  19. Nguyen CT, Weisenberger DJ, Velicescu M et al (2002) Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res 62, 6456-6461