Regulation of IKK-epsilon and TRAF6 functions by posttranslational modifications
Final Report Abstract
The work from this project has revealed several important insights into the function of IKKɛ and TRAF6. We found an LPS-induced ubiquitination of IKKɛ at 5 residues in the C-terminus of the kinase. While inducible ubiquitination is mediated by TRAF6, the PARP10 ADP Ribosyltransferase removes the ubiquitin chains. Further experiments suggest a role of IKKɛ ubiquitination for the LPS-inducible expression of selected IKKɛ target genes. The LPS-inducible phosphorylation of TRAF6 at S279 occurred in 2 waves, as detected using a selfmade phospho-specific antibody. A phosphomimicking TRAF6 mutant showed a reduced ability for IKKɛ ubiquitination, consistent with the concept that this modification serves to restrict TRAF6 E3 ligase activity. This modification also increase TRAF6 stability, thus allowing to steer the amount and activity of this enzyme, thus leading to profound effects on LPS-stimulated gene expression. In addition, published data from this project identified and characterized the modification of TBK1 by SUMO, the contribution of IKKɛ for ERK signaling and the contribution of TRAF6 for mRNA metabolism.
Publications
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(2013) Deregulated expression of TANK in glioblastomas triggers protumorigenic ERK1/2 and AKT signaling pathways. Oncogenesis Nov 11;2:e79
Stellzig, J., Chariot, A., Shostak, K., Göktuna, S.I., Renner, F., Acker, T., Pagenstecher, A. and M.L. Schmitz
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(2014) The intricate interplay between RNA viruses and NF-κB. Biochim. Biophys. Acta, 1843, 2754-2764
Schmitz, M.L., M. Kracht and V.V. Saul
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(2015) SUMO modification of TBK1 at the adaptor-binding C-terminal coiled-coil domain contributes to its antiviral activity. Biochim. Biophys. Acta 1853, 136–143
Saul, V.V., Niedenthal, R., Pich, A., Weber, F. and M.L. Schmitz
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(2016) K63-ubiquitylation and TRAF6 pathways regulate mammalian P-body formation and mRNA decapping. Mol. Cell 62, 943-957
Tenekeci, U., Poppe, M. Beuerlein, K., Buro, C., Müller, H., Weiser, H., Kettner-Buhrow, D., Porada, K., Newel, D., Xu, M., Chen, Z.J., Busch, J., Schmitz, M.L. and M. Kracht
