Research

Ubiquitin signaling in the NF-κB pathway

IkB ubiquitination, IKK and IkB ubiquitin ligase

NF-κB is a transcription factor that regulates a plethora of genes in response to diverse stimuli. Aberrant regulation of NF-κB has been linked to many human diseases, such as cancer and autoimmune diseases. NF-κB is normally sequestered in the cytoplasm by proteins of the IkB family. Upon stimulation, distinct signaling cascades converge on the IkB kinase complex (IKK), which phosphorylates IkBs and targets these inhibitors for degradation by the ubiquitin proteasome pathway. NF-κB then enters the nucleus to turn on downstream target genes. 

Representative Publications

Ubiquitin-mediated activation of TAK1 and IKK

Recently, we have focused on how IKK is regulated by different pathways. Interestingly, we found that ubiquitination activates IKK through a proteasome-independent mechanism. We found that TRAF6, an essential protein for NF-κB activation by interleukin-1b and Toll-like receptors (TLRs), is a ubiquitin E3 ligase that functions together with an E2 complex, Ubc13/Uev1A, to synthesize polyubiquitin chains linked through lysine 63 (K63) of ubiquitin. These ubiquitin chains bind to the TAB2 and TAB3 subunits of the TAK1 kinase complex, resulting in TAK1 kinase activation. TAK1 then phosphorylates and activates IKK. Recent research in our lab and others have supported a critical role of ‘non-degradative’ ubiquitination in the activation of TAK1 and IKK in different pathways, including those triggered by TNF receptor, T cell receptor, RIG-I like receptor, NOD-like receptors and DNA damage. 

Representative Publications

Representative Publications

IkB ubiquitination, IKK and IkB ubiquitin ligase

  • Chen, Z.J., Hagler, J. Palombella, V. J., Melandri, F., Scherer, D., Ballard, D., and Maniatis, T. (1995) Signal-induced site-specific phosphorylation targets IkBa to the ubiquitin-proteasome pathway. Genes & Dev. 9: 1586-1597
  • Chen, Z.J., Parent, L., and Maniatis, T. (1996) Site-specific phosphorylation of IkBa by a novel ubiquitination-dependent protein kinase activity. Cell 84, 853-862.
  • Spencer, E., Jiang, J., and Chen, Z.J. (1999) Signal-induced ubiquitination of IkBa by the F-box protein, Slimb/b-TrCP. Genes & Dev. 13, 284-294.

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Ubiquitin-mediated activation of TAK1 and IKK

  • Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., and Chen, Z.J. (2000) Activation of the IkB kinase complex requires a dimeric ubiquitin conjugating enzyme complex and the formation of a unique polyubiquitin chain. Cell 103, 351-361.
  • Wang, C., Deng, L., Hong, M. Akkaraju, G.R., Inoue, J-i., and Chen, Z.J. (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-351.
  • Sun, L., Deng, L., Ea, C-K., Xia, Z-P., and Chen, Z.J. (2004) The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Molecular Cell 14, 289-301.
  • Kanayama, A., Seth, R.B., Ea, C-K, Hong, M., Shaito, A., Deng, L., and Chen, Z.J. (2004) TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Molecular Cell 15, 535-548.
  • Ea, C-K., Deng, L., Xia, Z-P., Pineda, G., and Chen, Z.J. (2006) Activation of  IKK by TNFa requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Molecular Cell 22, 245-257.
  • Xu, M., Skaug, B., Zeng, W., and Chen, Z.J. (2009) A ubiquitin replacement strategy reveals distinct mechanisms of IKK activation by TNFa and IL-1b.Molecular Cell 36, 315-325.
  • Xia, Z.P., Sun, L., Chen, X., Pineda, G., Jiang, X., Adhikari, A., Zeng, W., and Chen, Z.J. (2009). Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 461, 114-119.
  • Skaug, B., Chen, J., Du, F., He, J, Ma, A., and Chen, Z.J. (2011) Direct, non-catalytic mechanism of IKK inhibition by A20. Molecular Cell 44, 559-571.

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