In vertebrates, the SLC15A4 gene codes for the peptide/histidine transporter 1 (PHT1) protein, which transport activity of di-/tripeptides and histidine across plasma and subcellular membranes has been generally described [1]. Recently, several studies have pointed out that the human SLC15A4 gene codes for a late endosome/lysosome carrier taking part in TLR7-, TLR9-, and NOD1-mediated pathways, thus putatively involved in inflammatory, immune and autoimmune diseases. Accordingly, SLC15A4/PHT1 altered activity has been associated to conditions such as type 2 diabetes, inflammatory bowel diseases (IBD) and systemic lupus erythematosus [2]. In mammals, the Slc15a4 genes are abundantly expressed by immune and nervous cells, in which they undergo alternative splicing (AS) events which physiological meaning is still unknown. Here, we report of a unique SLC15A4/PHT1 AS-mediated regulation which we found conserved from zebrafish to human. We show that this regulation is physiologically facilitated by the Nonsense-Mediated mRNA Decay (NMD) surveillance pathway, in human nervous-derived and immune-derived cells too; in these latter, both the canonical and AS variants are sensitive to inflammatory molecular triggers. Furthermore, in an IBD murine model, we show that GI inflammation seems to differentially affect the expression levels of the alternative SLC15A4/PHT1 gene products in different GI tracts. Overall, by unveiling the AS-NMD-mediated gene regulation, our findings might introduce a key analytical element for stepping forward the comprehension of the mechanism of intervention of SLC15A4/PHT1 in inflammatory and immune processes. [1] Verri T, Barca A, et al. (2017) Di- and tripeptide transport in vertebrates: the contribution of teleost fish models. J Comp Physiol B. 187(3):395-462. [2] Griffith AD, Zaidi AK, et al. (2018) A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice. Sci Rep. 8(1):14451.
Unveiling of the AS-NMD-mediated regulation of Peptide/Histidine Transporter 1 (SLC15A4/PHT1) gene products under physiological or inflammatory challenges
Barca A;Mazzei A;Croce V;Vacca F;Verri T.
2019-01-01
Abstract
In vertebrates, the SLC15A4 gene codes for the peptide/histidine transporter 1 (PHT1) protein, which transport activity of di-/tripeptides and histidine across plasma and subcellular membranes has been generally described [1]. Recently, several studies have pointed out that the human SLC15A4 gene codes for a late endosome/lysosome carrier taking part in TLR7-, TLR9-, and NOD1-mediated pathways, thus putatively involved in inflammatory, immune and autoimmune diseases. Accordingly, SLC15A4/PHT1 altered activity has been associated to conditions such as type 2 diabetes, inflammatory bowel diseases (IBD) and systemic lupus erythematosus [2]. In mammals, the Slc15a4 genes are abundantly expressed by immune and nervous cells, in which they undergo alternative splicing (AS) events which physiological meaning is still unknown. Here, we report of a unique SLC15A4/PHT1 AS-mediated regulation which we found conserved from zebrafish to human. We show that this regulation is physiologically facilitated by the Nonsense-Mediated mRNA Decay (NMD) surveillance pathway, in human nervous-derived and immune-derived cells too; in these latter, both the canonical and AS variants are sensitive to inflammatory molecular triggers. Furthermore, in an IBD murine model, we show that GI inflammation seems to differentially affect the expression levels of the alternative SLC15A4/PHT1 gene products in different GI tracts. Overall, by unveiling the AS-NMD-mediated gene regulation, our findings might introduce a key analytical element for stepping forward the comprehension of the mechanism of intervention of SLC15A4/PHT1 in inflammatory and immune processes. [1] Verri T, Barca A, et al. (2017) Di- and tripeptide transport in vertebrates: the contribution of teleost fish models. J Comp Physiol B. 187(3):395-462. [2] Griffith AD, Zaidi AK, et al. (2018) A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice. Sci Rep. 8(1):14451.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
