p300-mediated acetylation of COMMD1 regulates its stability, and the ubiquitylation and nucleolar translocation of the RelA NF-κB subunit.
Bottom Line: We show that p300 is required for stress-mediated ubiquitylation and nucleolar translocation of RelA, but that this effect is indirect.In contrast, tumour necrosis factor (TNF) has no effect on COMMD1 acetylation.Finally, we demonstrate these findings have relevance in a whole tissue setting.
Affiliation: Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.Show MeSH
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Mentions: Instead of RelA, we considered the possibility that p300 modulates COMMD1. Indeed, immunoprecipitation indicated that COMMD1 interacts with p300, that this interaction is greatly enhanced upon aspirin exposure (despite a decrease in total cellular levels of p300) and that this is associated with COMMD1 acetylation (Fig. 2A,B). To determine the role of this acetylation in nucleolar transport of RelA we firstly utilised a small interfering RNA (siRNA) approach. Surprisingly, we found that depletion of p300 alone caused a substantial reduction in basal and induced levels of COMMD1 (Fig. 2C) and thus, abrogated the COMMD1–RelA interaction (Fig. 2D). Use of an independent siRNA confirmed the substantial depletion of COMMD1 upon p300 knockdown (Fig. 2E). Furthermore, overexpression studies indicated this could be rescued by expression of wild-type p300, but not an acetylation defective mutant [deleted for the histone acetyltransferase domain (ΔHAT)] (Dornan et al., 2004) (Fig. 2F).
Affiliation: Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.