Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteasomal degradation.
Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteasomal degradation.
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DOI：
10.1007/s00018-011-0912-2
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发表时间：
2012-06
影响因子：
8
通讯作者：
Anrather, Josef
中科院分区：
文献类型：
--
作者：
Hochrainer, Karin;Racchumi, Gianfranco;Zhang, Sheng;Iadecola, Costantino;Anrather, Josef
Termination and resolution of inflammation is 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.
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通讯作者：
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