SLC15A4/PHT1 is a proton dependent histidine and oligopeptide transporter highly expressed in nervous and immune systems that has been recently associated with inflammatory bowel diseases, systemic lupus erythematosus and diabetes. In vertebrates, SLC15A4 genes are composed of eight exons and are subjected to alternative splicing events. However, the significance of alternative splicing in SLC15A4 function is still unknown. In this study, we investigated the role of alternative splicing in the regulation of SLC15A4 mRNA expression.

Alternatively spliced SLC15A4 transcripts in human, rat and zebrafish tissues were identified by RT-PCR, cloning and sequencing. Interestingly, we found that in all SLC15A4 genes analyzed the exon 3 is alternatively spliced to generate mRNA isoforms carrying a premature termination codon (PTC).

The SLC15A4 PTC-containing isoform of rat does not encode for protein but is targeted for degradation through the nonsense mediated mRNA decay (NMD) surveillance machinery. Moreover, over-expression of the rat SLC15A4 intron 2, involved with the exon 3 in the conserved SLC15A4 alternative splicing event, specifically decreased the mRNA level of the PTC-containing SLC15A4 isoform.

Overall, these results indicate that SLC15A4 levels are finely controlled by a complex regulatory mechanism involving alternative splicing, intron 2 activity and NMD system.