HSCARG Regulates NF-κB Activation by Promoting the Ubiquitination of RelA or COMMD1

Abstract

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-B, and negatively regulate COMMD1 by accelerating its ubiquitination and proteasome-dependent degradation. Interestingly, we observed that HSCARG also blocked basal and stimulus-coupled NF-B activation by promoting ubiquitination and degradation of the NF-B 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-B. 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-B activation. Meanwhile, COMMD1 was restored due to decreased cytoplasmic HSCARG levels and negatively regulated NF-B as well. Thus, NF-B activation was terminated efficiently. Our results indicate that HSCARG plays critical roles in regulation of NF-B in response to cellular redox changes by promoting ubiquitination and proteolysis of RelA or COMMD1.

Stamp2 Controls Macrophage Inflammation through Nicotinamide Adenine Dinucleotide Phosphate Homeostasis and Protects against Atherosclerosis

“…In contrast, there were no differences in TLR4 expression. It has been reported that when cellular NADPH levels are low, the NADPH sensor protein NMRAL1 (NmrA-like family domain-containing protein 1) translocates to the nucleus and targets p65 for degradation and furthermore releases COMMD1 (copper metabolism gene MURR1 domain containing protein 1) to inhibit NF-κB (Lian and Zheng, 2009; Zheng et al, 2007). As this protein may link increased NADPH levels to the pro-inflammatory phenotype, we determined regulation of NMRAL1 in cytosolic and nuclear fractions in Stamp2 −/− cells.…”

The phosphate makes a difference: cellular functions of NADP

“…As a consequence, AS is inhibited and NO production decreased. 3,61,62 Translocation of HSCARG from the cytoplasm to the nucleus has also been shown to terminate activation of transcription factor NF-κB, 63 thereby establishing a close link between the cellular redox state and gene regulation. NAD(P) has also been implicated in regulation of circadian rhythms.…”

Canine models of copper toxicosis for understanding mammalian copper metabolism

“…XIAP (Burstein et al 2004; Maine et al 2009), HSCARG (Lian and Zheng 2009), Clusterin (Zoubeidi et al 2010), and ARF (Huang et al 2008) were identified as COMMD1 interacting proteins regulating several components of this process.…”