Upstream open reading frames regulate translation of the long isoform of SLAMF1 mRNA that encodes costimulatory receptor CD150

Biochemistry (Mosc). 2014 Dec;79(12):1405-11. doi: 10.1134/S0006297914120165.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Antigens, CD / biosynthesis*
  • Antigens, CD / genetics*
  • Eukaryotic Initiation Factor-2 / deficiency
  • Eukaryotic Initiation Factor-4E / deficiency
  • Genes, Reporter / genetics
  • HEK293 Cells
  • Humans
  • Mutagenesis, Site-Directed
  • Open Reading Frames / genetics*
  • Protein Biosynthesis / genetics*
  • RNA Isoforms / genetics*
  • Receptors, Cell Surface / biosynthesis*
  • Receptors, Cell Surface / genetics*
  • Signaling Lymphocytic Activation Molecule Family Member 1

Substances

  • 5' Untranslated Regions
  • Antigens, CD
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-4E
  • RNA Isoforms
  • Receptors, Cell Surface
  • SLAMF1 protein, human
  • Signaling Lymphocytic Activation Molecule Family Member 1