Novel RNA-binding activity of NQ01 promotes SERPINA1 mRNA translation

NAD(P)H: quinone oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQOI target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINAI mRNA, encodes the serine protease inhibitor oc-1-antitrypsin, AlAT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3' untranslated region (UTR) and the coding region (CR) of SERPINAI mRNA. NQOI did not affect SERPINAI mRNA levels; instead, it enhanced the translation of SERPINAI mRNA, as NQOI silencing decreased the size of polysomes forming on SERPINAI mRNA and lowered the abundance of AlAT. Luciferase reporter analysis further indicated that NQOI regulates SERPINAI mRNA translation through the SERPINAI 3'UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of AlAT and increased activity of neutrophil elastase (NE), one of the main targets of AlAT. We propose that this novel mechanism of action of NQOI as an RNA-binding protein may help to explain its pleiotropic biological effects. Published by Elsevier Inc.