Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteasomal degradation. Academic Article uri icon

Overview

abstract

  • Termination and resolution of inflammation are tightly linked to the inactivation of one of its strongest inducers, NF-κB. While canonical post-stimulus inactivation is achieved by upregulation of inhibitory molecules that relocate NF-κB complexes to the cytoplasm, termination of the NF-κB 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-κB activity. By employing serine-to-alanine mutants, we found that hypo-phosphorylated nuclear RelA is monoubiquitinated on multiple lysine residues. Ubiquitination was reversed by IκBα expression and was reduced when nuclear translocation was inhibited. RelA monoubiquitination decreased NF-κB 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.

publication date

  • January 20, 2012

Research

keywords

  • NF-kappa B
  • Proteasome Endopeptidase Complex
  • Transcription Factor RelA
  • Ubiquitination

Identity

PubMed Central ID

  • PMC3621033

Scopus Document Identifier

  • 84862852850

Digital Object Identifier (DOI)

  • 10.1007/s00018-011-0912-2

PubMed ID

  • 22261743

Additional Document Info

volume

  • 69

issue

  • 12