Ubiquitin-dependent mechanism regulates rapid turnover of AU-rich cytokine mRNAs
AUTOR(ES)
Laroia, Gaurav
FONTE
The National Academy of Sciences
RESUMO
An AU rich element (ARE) in the 3′ noncoding region promotes the rapid degradation of mammalian cytokine and proto-oncogene mRNAs, such as tumor necrosis factor-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) and c-fos. Destabilization of ARE-mRNAs involves the association of ARE-binding proteins tristetraprolin or AUF1 and proteasome activity, of which the latter has not been characterized. Here, we show that the stability of a model short-lived mRNA containing the GM-CSF ARE was regulated by the level of ubiquitin-conjugating activity in the cell, which links ARE-mRNA decay to proteasome activity. Increased expression of a cytokine-inducible deubiquitinating protein (DUB) that impairs addition of ubiquitin to proteins fully blocked ARE-mRNA decay, whereas increased expression of a DUB that promotes ubiquitin addition to proteins strongly accelerated ARE-mRNA decay. ARE-mRNA turnover was found to be activated by the ubiquitin-addition reaction and blocked by the ubiquitin-removal reaction. Saturation of the ARE-mRNA decay machinery by high levels of ARE-mRNA, which is well established but not understood, was found to be relieved by increased expression of a DUB that promotes ubiquitin addition to proteins. Finally, inhibition of proteasome activity also blocked accelerated ARE-mRNA decay that is mediated by increased ubiquitin recycling. These results demonstrate that both ubiquitinating activity and proteasome activity are essential for rapid turnover of a model cytokine ARE-mRNA containing the GM-CSF ARE.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=122281Documentos Relacionados
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