title: IFN-α and lipopolysaccharide upregulate APOBEC3 mRNA through different signaling pathways.
abstract: APOBEC3 (A3) proteins are virus-restriction factors that provide intrinsic immunity against infections by viruses like HIV-1 and mouse mammary tumor virus. A3 proteins are inducible by inflammatory stimuli, such as LPS and IFN-α, via mechanisms that are not fully defined. Using genetic and pharmacological studies on C57BL/6 mice and cells, we show that IFN-α and LPS induce A3 via different pathways, independently of each other. IFN-α positively regulates mouse APOBEC3 (mA3) mRNA expression through IFN-αR/PKC/STAT1 and negatively regulates mA3 mRNA expression via IFN-αR/MAPKs-signaling pathways. Interestingly, LPS shows some variation in its regulatory behavior. Although LPS-mediated positive regulation of mA3 mRNA occurs through TLR4/TRIF/IRF3/PKC, it negatively modulates mA3 mRNA via TLR4/MyD88/MAPK-signaling pathways. Additional studies on human peripheral blood mononuclear cells reveal that PKC differentially regulates IFN-α and LPS induction of human A3A, A3F, and A3G mRNA expression. In summary, we identified important signaling targets downstream of IFN-αR and TLR4 that mediate A3 mRNA induction by both LPS and IFN-α. Our results provide new insights into the signaling targets that could be manipulated to enhance the intracellular store of A3 and potentially enhance A3 antiviral function in the host.
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Harshini V
authors.initials: HV
authors.lastname: Mehta
authors.forename: Philip H
authors.initials: PH
authors.lastname: Jones
authors.forename: Jerrold P
authors.initials: JP
authors.lastname: Weiss
authors.forename: Chioma M
authors.initials: CM
authors.lastname: Okeoma
mesh_terms: D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D016898:Interferon-alpha / Q000502:physiology*; D007424:Intracellular Fluid / Q000276:immunology / Q000821:virology; D008070:Lipopolysaccharides / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase