Molecular Basis of Cell and Developmental Biology
HSCARG Regulates NF-κB Activation by Promoting the Ubiquitination of RelA or COMMD1*

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The redox sensor protein HSCARG translocates from the cytoplasm to the nucleus in response to decreased cellular NADPH or increased nitric oxide, and is involved in protein regulation. However, the regulatory mechanism of HSCARG has remained elusive. In this report, through a yeast two-hybrid screen, HSCARG was found to associate with the copper metabolism gene MURR1 domain containing protein 1 (COMMD1), an inhibitor of NF-κB, and negatively regulate COMMD1 by accelerating its ubiquitination and proteasome-dependent degradation. Interestingly, we observed that HSCARG also blocked basal and stimulus-coupled NF-κB activation by promoting ubiquitination and degradation of the NF-κB subunit RelA. Further analyses showed that in cells under normal conditions, HSCARG localized mainly in the cytoplasm and acted as a negative regulator of COMMD1, and was distributed in the nucleus in small quantities to inhibit NF-κB. Although in response to intracellular redox changes by dehydroepiandrosterone or S-nitroso-N-acetylpenicillamine treatment, a large amount of HSCARG translocated to the nucleus, which terminated NF-κB activation. Meanwhile, COMMD1 was restored due to decreased cytoplasmic HSCARG levels and negatively regulated NF-κB as well. Thus, NF-κB activation was terminated efficiently. Our results indicate that HSCARG plays critical roles in regulation of NF-κB in response to cellular redox changes by promoting ubiquitination and proteolysis of RelA or COMMD1.

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This work was supported by National Science Foundation of China Grant 30670416, the National High Technology and Development Program of China Program numbers 863, 2006AA02A314 and 973, 2007CB914303, and International Centre for Genetic Engineering and Biotechnology (ICGEB) Project number CRP/CHN05-01.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.