RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization

Emad Y Alqassim,Brian D Lichty,A N M Nazmul H Khan,Bruce A Davidson,Eduardo Cortes Gomez,Tiffany R Emmons,Bora E Baysal,Abdulrahman Alahmari,Brahm H Segal,Kirsten B Moysich,Kelly L Singel,Qian Liu,Jianmin Wang,Shraddha Sharma,A J Robert Mcgray,Kunle Odunsi,Jaron Mark

doi:10.1038/s42003-020-01620-x

Abstract

Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.

Highlights

1234567890():,; Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses
In addition to IFNs, hypoxia and cellular crowding induces endogenous C>U RNA editing by A3A in monocytes and by A3G in natural killer cells[22,23,28]
We previously showed that IFN-γ and LPS induce RNA editing in M1 macrophages and that the level of editing in several sites is reduced with knockdown (KD) of A3A22

Summary

Introduction

1234567890():,; Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages. MicroRNA (miRNAs), DNA methylation and histone modification influence macrophage polarization[15] In addition to these well-characterized pathways for epigenetic modification, enzyme-regulated RNA editing may be another mechanism regulating macrophage responses. A3A-mediated RNA editing is endogeneously induced by IFN-γ during M1 macrophage polarization and by type 1 interferons (IFN-1) in monocytes/macrophages[22]. A3G-mediated RNA editing triggers a Warburg-like metabolic remodeling in HuT78 T cell lymphoma line[23] These findings suggest that APOBEC3-mediated RNA editing may play a role in hypoxia-induced or IFN-induced cell stress response. Humans have 10 APOBEC genes, but only A3A mediates RNA editing in monocytes and macrophages[22]

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Results

Conclusion