title: Upstream open reading frames regulate translation of the long isoform of SLAMF1 mRNA that encodes costimulatory receptor CD150.
abstract: More than 40% of human genes contain upstream open reading frames (uORF) in their 5'-untranslated regions (5'-UTRs) and at the same time express at least one truncated mRNA isoform containing no uORF. We studied translational regulation by four uORFs found in the 5'-UTR of full-length mRNA for SLAMF1, the gene encoding CD150 membrane protein. CD150 is a member of the CD2 superfamily, a costimulatory lymphocyte receptor, a receptor for measles virus, and a microbial sensor on macrophages. The SLAMF1 gene produces at least two mRNA isoforms that differ in their 5'-UTRs. In the long isoform of the SLAMF1 mRNA that harbors four uORFs in the 5'-UTR, the stop codon of uORF4 overlaps with the AUG codon of the main ORF forming a potential termination-reinitiation site UGAUG, while uORF2 and uORF3 start codons flank a sequence identical to Motif 1 from the TURBS regulatory element. TURBS was shown to be required for a coupled termination-reinitiation event during translation of polycistronic RNAs of some viruses. In a model cell system, reporter mRNA based on the 5'-UTR of SLAMF1 short isoform, which lacks any uORF, is translated 5-6 times more efficiently than the mRNA with 5'-UTR from the long isoform. Nucleotide substitutions disrupting start codons in either uORF2-4 result in significant increase in translation efficiency, while substitution of two nucleotides in TURBS Motif 1 leads to a 2-fold decrease in activity. These data suggest that TURBS-like elements can serve for translation control of certain cellular mRNAs containing uORFs.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia. kuprash@gmail.com.
authors.forename: L V
authors.initials: LV
authors.lastname: Putlyaeva
authors.forename: A M
authors.initials: AM
authors.lastname: Schwartz
authors.forename: K V
authors.initials: KV
authors.lastname: Korneev
authors.forename: M
authors.initials: M
authors.lastname: Covic
authors.forename: L A
authors.initials: LA
authors.lastname: Uroshlev
authors.forename: V Yu
authors.initials: VY
authors.lastname: Makeev
authors.forename: S E
authors.initials: SE
authors.lastname: Dmitriev
authors.forename: D V
authors.initials: DV
authors.lastname: Kuprash
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000172:deficiency; D039561:Eukaryotic Initiation Factor-4E / Q000172:deficiency; D017930:Genes, Reporter / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D016366:Open Reading Frames / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D059368:RNA Isoforms / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics*; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1
chemical_list: D020121:5' Untranslated Regions; D015703:Antigens, CD; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D059368:RNA Isoforms; D011956:Receptors, Cell Surface; C000604059:SLAMF1 protein, human; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1