Published online 4 July 2006
Published by Oxford University Press 2006
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Metabolic regulation of ApoB mRNA editing is associated with phosphorylation of APOBEC-1 complementation factor
1 Department of Biochemistry and Biophysics, University of Rochester Rochester, NY 14642, USA 2 Department of Pathology and Laboratory Medicine, University of Rochester Rochester, NY 14642, USA 3 Department of Toxicology, University of Rochester Rochester, NY 14642, USA 4 The Environmental Health Sciences Center, University of Rochester Rochester, NY 14642, USA 5 James P. Wilmot Cancer Center, University of Rochester Rochester, NY 14642, USA
*To whom correspondence should be addressed. Tel: +1 585 275 4267; Fax: +1 585 275 6007; Email: harold.smith{at}rochester.edu
Received March 7, 2006. Revised April 28, 2006. Accepted May 19, 2006.
Apolipoprotein B (apoB) mRNA editing is a nuclear event that minimally requires the RNA substrate, APOBEC-1 and APOBEC-1 Complementation Factor (ACF). The co-localization of these macro-molecules within the nucleus and the modulation of hepatic apoB mRNA editing activity have been described following a variety of metabolic perturbations, but the mechanism that regulates editosome assembly is unknown. APOBEC-1 was effectively co-immunoprecipitated with ACF from nuclear, but not cytoplasmic extracts. Moreover, alkaline phosphatase treatment of nuclear extracts reduced the amount of APOBEC-1 co-immunoprecipitated with ACF and inhibited in vitro editing activity. Ethanol stimulated apoB mRNA editing was associated with a 2- to 3-fold increase in ACF phosphorylation relative to that in control primary hepatocytes. Significantly, phosphorylated ACF was restricted to nuclear extracts where it co-sedimented with 27S editing competent complexes. Two-dimensional phosphoamino acid analysis of ACF immunopurified from hepatocyte nuclear extracts demonstrated phosphorylation of serine residues that was increased by ethanol treatment. Inhibition of protein phosphatase I, but not PPIIA or IIB, stimulated apoB mRNA editing activity coincident with enhanced ACF phosphorylation in vivo. These data demonstrate that ACF is a metabolically regulated phosphoprotein and suggest that this post-translational modification increases hepatic apoB mRNA editing activity by enhancing ACF nuclear localization/retention, facilitating the interaction of ACF with APOBEC-1 and thereby increasing the probability of editosome assembly and activity.
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