title: CUGBP1 is required for IFNbeta-mediated induction of dominant-negative CEBPbeta and suppression of SIV replication in macrophages.
abstract: Productive HIV replication in the CNS occurs very early after infection, yet HIV-associated cognitive disorders do not typically manifest until the development of AIDS, suggesting that mechanisms exist in the CNS to control HIV replication and associated virus-induced pathological changes during the acute and asymptomatic stages of disease. Using an established SIV/macaque model of HIV dementia, we recently demonstrated that the mechanisms regulating virus replication in the brain at these stages involve the production of IFNbeta, which induces the truncated, dominant-negative isoform of C/EBPbeta, also referred to as LIP (liver-enriched transcriptional inhibitory protein). Alternative translation of C/EBPbeta mRNA and increased production of LIP can be mediated by CUGBP1 (CUG-repeat RNA-binding protein 1). Because IFNbeta induces the inhibitory C/EBPbeta in macrophages, we considered the possibility that IFNbeta signaling regulates the activity of CUGBP1, resulting in increased expression of LIP and suppression of SIV replication. In this study, we report that IFNbeta induces LIP and suppresses active SIV replication in primary macrophages from rhesus macaques. Further, we demonstrate that IFNbeta induces the phosphorylation of CUGBP1 and the formation of CUGBP1-C/EBPbeta mRNA complexes in the human monocytic U937 cell line. Finally, we demonstrate that CUGBP1 is not only required for IFNbeta-mediated induction of LIP but also for IFNbeta-mediated suppression of SIV replication. These results suggest that CUGBP1 is a previously unrecognized downstream effector of IFNbeta signaling in primary macrophages that likely plays a pivotal role in innate immune responses that control acute HIV/SIV replication in the brain.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Justyna M
authors.initials: JM
authors.lastname: Dudaronek
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Barber
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis* / Q000235:genetics; D000067879:CELF1 Protein; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects* / Q000276:immunology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D000067879:CELF1 Protein; C102843:CELF1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D016899:Interferon-beta