Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation

Abstract

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 NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, 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 SERPINA1 mRNA. NQO1 did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA, as NQO1 silencing decreased the size of polysomes forming on SERPINA1 mRNA and lowered the abundance of A1AT. Luciferase reporter analysis further indicated that NQO1 regulates SERPINA1 mRNA translation through the SERPINA1 3′UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of A1AT and increased activity of neutrophil elastase (NE), one of the main targets of A1AT. We propose that this novel mechanism of action of NQO1 as RNA-binding protein may help to explain its pleiotropic biological effects.

Multi-omics Analysis of the Intermittent Fasting Response in Mice Identifies an Unexpected Role for HNF4α

“…HNF4a is a key transcription factor upstream of a1-antitrypsin (SERPINA1) production in hepatocytes (Odom et al, 2004;Shih et al, 2000). The NQO1 protein that we observed as increased in abundance after EODF is also known to regulate the translation of the SERPINA1 mRNA (Di Francesco et al, 2016). Our EODF animals displayed a $3-fold decrease in the plasma levels of a1-antitrypsin after only 2 weeks of EODF treatment.…”

Preliminary investigation of the function of hsa_circ_0006215 in pancreatic cancer

“…SERPINA1 expression is low in high-grade invasive ovarian epithelial cell carcinoma, but high in low malignant potential tumors. However, overexpression of SERPINA1 in vitro is able to promote the invasion and metastasis of tumor cells (54). For certain types of tumor, SERPINA1 is effective for treatment with target enzymes directly.…”

A comparative analysis of in vitro toxicity of diesel exhaust particles from combustion of 1st- and 2nd-generation biodiesel fuels in relation to their physicochemical properties—the FuelHealth project

“…Similarly, upregulated expression of GSR is an indicator of antioxidant responses as GSR plays a critical role in the antioxidant defense not only by reducing oxidized glutathione (GSSG) but also by clearance of electrophilic metabolite (Drozd et al 2016 ). Further signs of antioxidant responses include overexpression of HMOX1, which is considered one of the most sensitive and reliable indicators of cellular oxidative stress (Maamoun et al 2016 ), TXNRD1, a pivotal intracellular redox sensor and antioxidant enzyme (Schmidt 2015 ), NQO1, which is essential for cell defense against ROS (Di Francesco et al 2016 ), and FTH1, a major iron storage protein that can protect cells from the toxic effects of iron as well as other free radical producing stresses (Funauchi et al 2015 ). In addition, downregulation of the pro-apoptotic BNIP3L, which plays an important role in hypoxia-dependent cell death (Bellot et al 2009 ) and upregulation of SQSTM1, a multifunctional adapter protein that accumulates following autophagy inhibition (Duleh et al 2016 ), was also observed.…”