title: Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway.
abstract: Programmed -1 ribosomal frameshift (-1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a -1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA-miRNA interaction suggests that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional -1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells.
authors.affiliation: 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2].
authors.forename: Ashton Trey
authors.initials: AT
authors.lastname: Belew
authors.affiliation: 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] Department of Biotechnology and Microbiology, Vilnius University, Vilnius, LT 03101, Lithuania [3].
authors.forename: Arturas
authors.initials: A
authors.lastname: Meskauskas
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Sharmishtha
authors.initials: S
authors.lastname: Musalgaonkar
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Advani
authors.affiliation: 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] VIB Center for the Biology of Disease, KU Leuven, Campus Gasthuisberg, Herestraat 49, bus 602, 3000 Leuven, Belgium.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Sulima
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors.forename: Wojciech K
authors.initials: WK
authors.lastname: Kasprzak
authors.affiliation: Basic Research Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Shapiro
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Dinman
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002470:Cell Survival; D018389:Codon, Nonsense / Q000235:genetics; D018965:Frameshifting, Ribosomal / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D059365:Nonsense Mediated mRNA Decay; D009690:Nucleic Acid Conformation; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics; D038621:Regulatory Sequences, Ribonucleic Acid; D012270:Ribosomes / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D035683:MicroRNAs; D012333:RNA, Messenger; D019713:Receptors, CCR5; D018123:Receptors, Interleukin; D038621:Regulatory Sequences, Ribonucleic Acid