A 3′UTR polymorphism disrupts IRF2BP2 autoregulation through an eIF4H translational enhancer

IntroductionInterferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the interferon response and inflammation. Individuals who carry 2 copies of a genetic variant (rs3045215) that deletes 9 nucleotides from the long 3′UTR of IRF2BP2 have lower IRF2BP2 protein expression in white blood cells and increased risk of coronary atherosclerosis and calcification.Methods and ResultsRNAfold revealed that the deletion variant of IRF2BP2 disrupts an RNA stem-loop structure that can recruit the eukaryotic initiation factor 4H (eIF4H) to facilitate translation. siRNA knockdown of eIF4H reduced expression of endogenous IRF2BP2 protein. Similarly, it impaired translation of a luciferase reporter bearing the whole 3′UTR of IRF2BP2 but had no effect on one bearing the 9-nucleotide deletion variant (rs3045215). This deletion variant happens to be co-inherited with an IRF2BP2 coding variant that changes proline to serine at position 78. Overexpression of either isoform of IRF2BP2 (Pro78 or Ser78) suppressed translation of the luciferase reporter containing the whole IRF2BP2 3′UTR to the same level but had no effect on the deletion-bearing reporter. RNA gel mobility shift assay using cytosolic extracts of LPS-stimulated THP1 macrophages revealed that the 9-nucleotide deletion variant prevents endogenous IRF2BP2 protein from interacting with its own 3′UTR RNA sequences.ConclusionThe rs3045215 9-nucleotide deletion that increases the risk of heart disease abolishes IRF2BP2 autoregulation through an eIF4H-dependent translational enhancer.