Heterologous SUMO-2/3-Ubiquitin Chains Optimize IκBα Degradation and NF-κB Activity

Fabienne Aillet, Fernando Lopitz-Otsoa, Isabel Egaña, Roland Hjerpe, Paul Fraser, Ron T. Hay, Manuel S. Rodriguez, Valerie Lang

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    41 Citations (Scopus)

    Abstract

    The NF-?B pathway is regulated by SUMOylation at least at three levels: the inhibitory molecule I?Ba, the IKK subunit ?/NEMO and the p52 precursor p100. Here we investigate the role of SUMO-2/3 in the degradation of I?Ba and activation of NF-?B mediated by TNFa. We found that under conditions of deficient SUMOylation, an important delay in both TNFa-mediated proteolysis of I?Ba and NF-?B dependent transcription occurs. In vitro and ex vivo approaches, including the use of ubiquitin-traps (TUBEs), revealed the formation of chains on I?Ba containing SUMO-2/3 and ubiquitin after TNFa stimulation. The integration of SUMO-2/3 appears to promote the formation of ubiquitin chains on I?Ba after activation of the TNFa signalling pathway. Furthermore, heterologous chains of SUMO-2/3 and ubiquitin promote a more efficient degradation of I?Ba by the 26S proteasome in vitro compared to chains of either SUMO-2/3 or ubiquitin alone. Consistently, Ubc9 silencing reduced the capture of I?Ba modified with SUMO-ubiquitin hybrid chains that display a defective proteasome-mediated degradation. Thus, hybrid SUMO-2/3-ubiquitin chains increase the susceptibility of modified I?Ba to the action of 26S proteasome, contributing to the optimal control of NF-?B activity after TNFa-stimulation.
    Original languageEnglish
    Article numbere51672
    JournalPLoS ONE
    Volume7
    Issue number12
    DOIs
    Publication statusPublished - 20 Dec 2012

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    Aillet, F., Lopitz-Otsoa, F., Egaña, I., Hjerpe, R., Fraser, P., Hay, R. T., Rodriguez, M. S., & Lang, V. (2012). Heterologous SUMO-2/3-Ubiquitin Chains Optimize IκBα Degradation and NF-κB Activity. PLoS ONE, 7(12), [e51672]. https://doi.org/10.1371/journal.pone.0051672