Translational regulation of complement protein C2 expression by differential utilization of the 5'-untranslated region of mRNA

A recently isolated cDNA for human complement protein C2, C2HL5-3, has an unusually long 5'-untranslated region (UTR) containing four open reading frames upstream of the authentic initiation codon. Here we report that deletion of the 5'-UTR of C2HL5-3 resulted in a 10-fold enhancement in the translational efficiency of C2 in transient eukaryotic cellular assays. Elimination of the open reading frames in the 5'-UTR by site-directed mutagenesis of the initiation codons did not affect C2 synthesis in this assay system, indicating that other structural elements in this region are responsible for translational control. We also show that several C2 mRNAs of varying length in the 5'-UTR, including an alternative C2 mRNA expressing a considerably shorter 5'-UTR, are present in the liver and that the shorter C2 mRNA is the only C2 message found in U937 cells. These results suggest that tissue-specific utilization of alternative transcriptional start sites results in differential translational efficiencies of C2 and may provide insights into the tissue- and stimulus-specific regulation of eukaryotic gene expression.