Monoubiquitination of nuclear RelA negatively regulates NF-?B activity independent of proteasomal degradation.

ABSTRACT: Termination and resolution of inflammation are tightly linked to the inactivation of one of its strongest inducers, NF-?B. While canonical post-stimulus inactivation is achieved by upregulation of inhibitory molecules that relocate NF-?B complexes to the cytoplasm, termination of the NF-?B response can also be accomplished directly in the nucleus by posttranslational modifications, e.g., ubiquitination of the RelA subunit. Here we reveal a functional role for RelA monoubiquitination in regulating NF-?B activity. By employing serine-to-alanine mutants, we found that hypo-phosphorylated nuclear RelA is monoubiquitinated on multiple lysine residues. Ubiquitination was reversed by I?B? expression and was reduced when nuclear translocation was inhibited. RelA monoubiquitination decreased NF-?B transcriptional activity despite prolonged nuclear presence and independently of RelA degradation, possibly through decreased CREB-binding protein (CBP) co-activator binding. Polyubiquitin-triggered proteasomal degradation has been proposed as a model for RelA inactivation. However, here we show that proteasomal inhibition, similar to RelA hypo-phosphorylation, resulted in nuclear translocation and monoubiquitination of RelA. These findings indicate a degradation-independent mechanism for regulating the activity of nuclear RelA by ubiquitination.

SUBMITTER: Hochrainer K 

PROVIDER: S-EPMC3621033 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature