[en] The Elongator complex is required for proper development of the cerebral cortex. Interfering with its activity in vivo delays the migration of postmitotic projection neurons, at least through a defective alpha-tubulin acetylation. However, this complex is already expressed by cortical progenitors where it may regulate the early steps of migration by targeting additional proteins. Here we report that connexin-43 (Cx43), which is strongly expressed by cortical progenitors and whose depletion impairs projection neuron migration, requires Elongator expression for its proper acetylation. Indeed, we show that Cx43 acetylation is reduced in the cortex of Elp3cKO embryos, as well as in a neuroblastoma cell line depleted of Elp1 expression, suggesting that Cx43 acetylation requires Elongator in different cellular contexts. Moreover, we show that histones deacetylase 6 (HDAC6) is a deacetylase of Cx43. Finally, we report that acetylation of Cx43 regulates its membrane distribution in apical progenitors of the cerebral cortex.
Research center :
Giga-Neurosciences et GIGA Molecular Biology of Diseases
Alstrom, J. S., Stroemlund, L. W., Nielsen, M. S., and MacAulay, N. (2015). Protein kinase C-dependent regulation of connexin43 gap junctions and hemichannels. Biochem. Soc. Trans. 43, 519–523. doi: 10.1042/BST20150040
Cai, K., Wan, Y., Wang, Z., Wang, Y., Zhao, X., and Bao, X. (2014). C5a promotes the proliferation of human nasopharyngeal carcinoma cells through PCAF-mediated STAT3 acetylation. Oncol. Rep. 32, 2260–2266. doi: 10.3892/or.2014.3420
Cina, C., Maass, K., Theis, M., Willecke, K., Bechberger, J. F., and Naus, C. C. (2009). Involvement of the cytoplasmic C-terminal domain of connexin43 in neuronal migration. J. Neurosci. 29, 2009–2021. doi: 10.1523/JNEUROSCI. 5025-08.2009
Close, P., Hawkes, N., Cornez, I., Creppe, C., Lambert, C. A., Rogister, B., et al. (2006). Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol. Cell 22, 521–531. doi: 10.1016/j.molcel.2006.04.017
Codd, R., Braich, N., Liu, J., Soe, C. Z., and Pakchung, A. A. (2009). Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int. J. Biochem. Cell Biol. 41, 736–739. doi: 10.1016/j.biocel.2008. 05.026
Colussi, C., Rosati, J., Straino, S., Spallotta, F., Berni, R., Stilli, D., et al. (2011). Nepsilon-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart. Proc. Natl. Acad. Sci. U S A 108, 2795–2800. doi: 10.1073/pnas.1013124108
Cotrina, M. L., Lin, J. H., and Nedergaard, M. (2008). Adhesive properties of connexin hemichannels. Glia 56, 1791–1798. doi: 10.1002/glia.20728
Creppe, C., Malinouskaya, L., Volvert, M. L., Gillard, M., Close, P., Malaise, O., et al. (2009). Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. Cell 136, 551–564. doi: 10.1016/j. cell.2008.11.043
Delaunay, S., Rapino, F., Tharun, L., Zhou, Z., Heukamp, L., Termathe, M., et al. (2016). Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer. J. Exp. Med. 213, 2503–2523. doi: 10. 1084/jem.20160397
Elias, L. A., and Kriegstein, A. R. (2008). Gap junctions: multifaceted regulators of embryonic cortical development. Trends Neurosci. 31, 243–250. doi: 10.1016/j. tins.2008.02.007
Elias, L. A., Turmaine, M., Parnavelas, J. G., and Kriegstein, A. R. (2010). Connexin 43 mediates the tangential to radial migratory switch in ventrally derived cortical interneurons. J. Neurosci. 30, 7072–7077. doi: 10.1523/JNEUROSCI. 5728-09.2010
Elias, L. A., Wang, D. D., and Kriegstein, A. R. (2007). Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448, 901–907. doi: 10.1038/nature06063
Ge, X., Jin, Q., Zhang, F., Yan, T., and Zhai, Q. (2009). PCAF acetylates β-catenin and improves its stability. Mol. Biol. Cell 20, 419–427. doi: 10.1091/mbc.e08-08-0792
Glatt, S., and Müller, C. W. (2013). Structural insights into Elongator function. Curr. Opin. Struct. Biol. 23, 235–242. doi: 10.1016/j.sbi.2013.02.009
Glatt, S., Séraphin, B., and Müller, C. W. (2012). Elongator: transcriptional or translational regulator? Transcription 3, 273–276. doi: 10.4161/trns.21525
Gnad, F., Gunawardena, J., and Mann, M. (2011). PHOSIDA 2011: the posttranslational modification database. Nucleic Acids Res. 39, D253–D260. doi: 10.1093/nar/gkq1159
Goodenough, D. A., and Paul, D. L. (2003). Beyond the gap: functions of unpaired connexon channels. Nat. Rev. Mol. Cell Biol. 4, 285–294. doi: 10.1038/nrm1072
Götz, M., and Huttner, W. B. (2005). The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777–788. doi: 10.1038/nrm1739
Hébert, J. M., and McConnell, S. K. (2000). Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev. Biol. 222, 296–306. doi: 10.1006/dbio.2000.9732
Jiménez-Canino, R., Lorenzo-Díaz, F., Jaisser, F., Farman, N., Giraldez, T., and Alvarez de la Rosa, D. (2016). Histone deacetylase 6-controlled Hsp90 acetylation significantly alters mineralocorticoid receptor subcellular dynamics but not its transcriptional activity. Endocrinology 157, 2515–2532. doi: 10.1210/en.2015-2055
Johnstone, S. R., Billaud, M., Lohman, A. W., Taddeo, E. P., and Isakson, B. E. (2012). Posttranslational modifications in connexins and pannexins. J. Membr. Biol. 245, 319–332. doi: 10.1007/s00232-012-9453-3
Kameritsch, P., Pogoda, K., and Pohl, U. (2012). Channel-independent influence of connexin 43 on cell migration. Biochim. Biophys. Acta 1818, 1993–2001. doi: 10.1016/j.bbamem.2011.11.016
Kovacs, J. J., Murphy, P. J., Gaillard, S., Zhao, X., Wu, J. T., Nicchitta, C. V., et al. (2005). HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607. doi: 10.1016/j. molcel.2005.04.021
Kriegstein, A. R., and Noctor, S. C. (2004). Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 27, 392–399. doi: 10.1016/j.tins.2004. 05.001
Ladang, A., Rapino, F., Heukamp, L. C., Tharun, L., Shostak, K., Hermand, D., et al. (2015). Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. J. Exp. Med. 212, 2057–2075. doi: 10.1084/jem.20142288
Laguesse, S., Creppe, C., Nedialkova, D. D., Prévot, P. P., Borgs, L., Huysseune, S., et al. (2015). A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev. Cell 35, 553–567. doi: 10.1016/j.devcel.2015.11.005
Laird, D. W. (2006). Life cycle of connexins in health and disease. Biochem. J. 394, 527–543. doi: 10.1042/bj20051922
Leithe, E. (2016). Regulation of connexins by the ubiquitin system: implications for intercellular communication and cancer. Biochim. Biophys. Acta 1865, 133–146. doi: 10.1016/j.bbcan.2016.02.001
Li, G., Jiang, H., Chang, M., Xie, H., and Hu, L. (2011). HDAC6 alpha-tubulin deacetylase: a potential therapeutic target in neurodegenerative diseases. J. Neurol. Sci. 304, 1–8. doi: 10.1016/j.jns.2011.02.017
Li, M., Luo, J., Brooks, C. L., and Gu, W. (2002). Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem. 277, 50607–50611. doi: 10.1074/jbc. c200578200
Li, L., and Yang, X. J. (2016). Molecular and functional characterization of histone deacetylase 4 (HDAC4). Methods Mol. Biol. 1436, 31–45. doi: 10.1007/978-1-4939-3667-0_4
Lin, J. H., Takano, T., Cotrina, M. L., Arcuino, G., Kang, J., Liu, S., et al. (2002). Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells. J. Neurosci. 22, 4302–4311.
Liu, J. S. (2011). Molecular genetics of neuronal migration disorders. Curr. Neurol. Neurosci. Rep. 11, 171–178. doi: 10.1007/s11910-010-0176-5
Liu, X., Hashimoto-Torii, K., Torii, M., Ding, C., and Rakic, P. (2010). Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors. J. Neurosci. 30, 4197–4209. doi: 10.1523/JNEUROSCI. 4187-09.2010
Liu, X., Sun, L., Torii, M., and Rakic, P. (2012). Connexin 43 controls the multipolar phase of neuronal migration to the cerebral cortex. Proc. Natl. Acad. Sci. U S A 109, 8280–8285. doi: 10.1073/pnas.1205880109
Lohman, A. W., Straub, A. C., and Johnstone, S. R. (2016). Identification of connexin43 phosphorylation and S-nitrosylation in cultured primary vascular cells. Methods Mol. Biol. 1437, 97–111. doi: 10.1007/978-1-4939-3664-9_7
Menzies, K. J., Zhang, H., Katsyuba, E., and Auwerx, J. (2016). Protein acetylation in metabolism - metabolites and cofactors. Nat. Rev. Endocrinol. 12, 43–60. doi: 10.1038/nrendo.2015.181
Meraviglia, V., Azzimato, V., Colussi, C., Florio, M. C., Binda, A., Panariti, A., et al. (2015). Acetylation mediates Cx43 reduction caused by electrical stimulation. J. Mol. Cell. Cardiol. 87, 54–64. doi: 10.1016/j.yjmcc.2015.08.001
Miskiewicz, K., Jose, L. E., Bento-Abreu, A., Fislage, M., Taes, I., Kasprowicz, J., et al. (2011). ELP3 controls active zone morphology by acetylating the ELKS family member Bruchpilot. Neuron 72, 776–788. doi: 10.1016/j.neuron.2011.10.010
Molyneaux, B. J., Arlotta, P., Menezes, J. R., and Macklis, J. D. (2007). Neuronal subtype specification in the cerebral cortex. Nat. Rev. Neurosci. 8, 427–437. doi: 10.1038/nrn2151
Moon, H. M., and Wynshaw-Boris, A. (2013). Cytoskeleton in action: lissencephaly, a neuronal migration disorder. Wiley Interdiscip. Rev. Dev. Biol. 2, 229–245. doi: 10.1002/wdev.67
Nguyen, L., Humbert, S., Saudou, F., and Chariot, A. (2010). Elongator— an emerging role in neurological disorders. Trends Mol. Med. 16, 1–6. doi: 10.1016/j.molmed.2009.11.002
Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S., and Kriegstein, A. R. (2001). Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720. doi: 10.1038/35055553
Ohtaka-Maruyama, C., and Okado, H. (2015). Molecular pathways underlying projection neuron production and migration during cerebral cortical development. Front. Neurosci. 9:447. doi: 10.3389/fnins.2015.00447
Orellana, J. A., Martinez, A. D., and Retamal, M. A. (2013). Gap junction channels and hemichannels in the CNS: regulation by signaling molecules. Neuropharmacology 75, 567–582. doi: 10.1016/j.neuropharm.2013.02.020
Oyamada, M., Oyamada, Y., and Takamatsu, T. (2005). Regulation of connexin expression. Biochim. Biophys. Acta 1719, 6–23. doi: 10.1016/j.bbamem.2005. 11.002
Petrakis, T. G., Wittschieben, B. O., and Svejstrup, J. Ø. (2004). Molecular architecture, structure-function relationship, and importance of the Elp3 subunit for the RNA binding of holo-elongator. J. Biol. Chem. 279, 32087–32092. doi: 10.1074/jbc.M403361200
Qi, G. J., Chen, Q., Chen, L. J., Shu, Y., Bu, L. L., Shao, X. Y., et al. (2016). Phosphorylation of connexin 43 by Cdk5 modulates neuronal migration during embryonic brain development. Mol. Neurobiol. 53, 2969–2982. doi: 10.1007/s12035-015-9190-6
Qiang, L., Banks, A. S., and Accili, D. (2010). Uncoupling of acetylation from phosphorylation regulates FoxO1 function independent of its subcellular localization. J. Biol. Chem. 285, 27396–27401. doi: 10.1074/jbc.M110.140228
Ribeiro-Rodrigues, T. M., Catarino, S., Pinho, M. J., Pereira, P., and Girao, H. (2015). Connexin 43 ubiquitination determines the fate of gap junctions: restrict to survive. Biochem. Soc. Trans. 43, 471–475. doi: 10.1042/BST20150036
Rinaldi, F., Hartfield, E. M., Crompton, L. A., Badger, J. L., Glover, C. P., Kelly, C. M., et al. (2014). Cross-regulation of Connexin43 and beta-catenin influences differentiation of human neural progenitor cells. Cell Death Dis. 5:e1017. doi: 10.1038/cddis.2013.546
Roche, J., and Bertrand, P. (2016). Inside HDACs with more selective HDAC inhibitors. Eur. J. Med. Chem. 121, 451–483. doi: 10.1016/j.ejmech.2016.05.047
Rouach, N., Avignone, E., Meme, W., Koulakoff, A., Venance, L., Blomstrand, F., et al. (2002). Gap junctions and connexin expression in the normal and pathological central nervous system. Biol. Cell 94, 457–475. doi: 10.1016/s0248-4900(02)00016-3
Santiago, M. F., Alcami, P., Striedinger, K. M., Spray, D. C., and Scemes, E. (2010). The carboxyl-terminal domain of connexin43 is a negative modulator of neuronal differentiation. J. Biol. Chem. 285, 11836–11845. doi: 10.1074/jbc. M109.058750
Simon, R. P., Robaa, D., Alhalabi, Z., Sippl, W., and Jung, M. (2016). KATching-Up on small molecule modulators of lysine acetyltransferases. J. Med. Chem. 59, 1249–1270. doi: 10.1021/acs.jmedchem.5b01502
Solan, J. L., and Lampe, P. D. (2009). Connexin43 phosphorylation: structural changes and biological effects. Biochem. J. 419, 261–272. doi: 10.1042/BJ20082319
Sosinsky, G. E., Solan, J. L., Gaietta, G. M., Ngan, L., Lee, G. J., Mackey, M. R., et al. (2007). The C-terminus of connexin43 adopts different conformations in the Golgi and gap junction as detected with structure-specific antibodies. Biochem. J. 408, 375–385. doi: 10.1042/bj20070550
Sterner, D. E., and Berger, S. L. (2000). Acetylation of histones and transcription-related factors. Microbiol. Mol. Biol. Rev. 64, 435–459. doi: 10.1128/mmbr.64.2.435-459.2000
Sutor, B., and Hagerty, T. (2005). Involvement of gap junctions in the development of the neocortex. Biochim. Biophys. Acta 1719, 59–68. doi: 10.1016/j.bbamem.2005.09.005
Tielens, S., Huysseune, S., Godin, J. D., Chariot, A., Malgrange, B., and Nguyen, L. (2016). Elongator controls cortical interneuron migration by regulating actomyosin dynamics. Cell Res. 26, 1131–1148. doi: 10.1038/cr.2016.112
Viatour, P., Legrand-Poels, S., van Lint, C., Warnier, M., Merville, M. P., Gielen, J., et al. (2003). Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3. J. Biol. Chem. 278, 46541–46548. doi: 10.1074/jbc.M306381200
Wang, L. X., Wang, J., Qu, T. T., Zhang, Y., and Shen, Y. F. (2014). Reversible acetylation of Lin28 mediated by PCAF and SIRT1. Biochim. Biophys. Acta 1843, 1188–1195. doi: 10.1016/j.bbamcr.2014.03.001
Winkler, G. S., Kristjuhan, A., Erdjument-Bromage, H., Tempst, P., and Svejstrup, J. Q. (2002). Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proc. Natl. Acad. Sci. U S A 99, 3517–3522. doi: 10.1073/pnas.022042899
Yao, Y. L., and Yang, W. M. (2011). Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their nonhistone substrates. J. Biomed. Biotechnol. 2011:146493. doi: 10.1155/2011/146493
Zhang, S., Sun, G., Wang, Z., Wan, Y., Guo, J., and Shi, L. (2015). PCAF-mediated Akt1 acetylation enhances the proliferation of human glioblastoma cells. Tumour Biol. 36, 1455–1462. doi: 10.1007/s13277-014-2522-8
Zhang, X., Yuan, Z., Zhang, Y., Yong, S., Salas-Burgos, A., Koomen, J., et al. (2007). HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol. Cell 27, 197–213. doi: 10.1016/j.molcel.2007.05.033