Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy.
MRH-Microbiome Research Hub, University of Parma, Parma, Italy.
Am J Physiol Cell Physiol. 2023 Aug 1;325(2):C550-C562. doi: 10.1152/ajpcell.00169.2023. Epub 2023 Jul 17.
/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na (symport) and H (antiport). Its preferential substrates are not only amino acids with side chains containing amide (glutamine and asparagine) or imidazole (histidine) groups, but also serine, glycine, and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/β-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis, and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. We review the functional role of the SNAT5 transporter in pathophysiology and propose that, due to its peculiar operational and regulatory features, SNAT5 may play important pro-cancer roles when expressed either in neoplastic or in stromal cells of glutamine-auxotroph tumors. The transporter /SNAT5 provides net influx or efflux of glutamine, asparagine, and serine. These amino acids are of particular metabolic relevance in several conditions. Changes in transporter expression or activity have been described in selected types of human cancers, where SNAT5 can mediate amino acid exchanges between tumor and stromal cells, thus providing a potential therapeutic target. This is the first review that recapitulates the characteristics and roles of the transporter in physiology and pathology.
/SNAT5 是一种系统 N 转运体，可介导中性氨基酸的净内向或外向跨膜通量，与 Na（共转运）和 H（反转运）偶联。其优先底物不仅是含有酰胺（谷氨酰胺和天冬酰胺）或咪唑（组氨酸）基团的氨基酸，而且丝氨酸、甘氨酸和丙氨酸也由载体转运。在胰腺、肠道、大脑、肝脏、骨髓和胎盘表达，其在 mRNA 和蛋白质水平上受 mTORC1 和 WNT/β-catenin 途径调节，对 pH 值、营养应激、炎症和缺氧敏感。在慢性炎症性疾病、妊娠并发症、慢性代谢性酸中毒和营养不良等病理状态下发现 SNAT5 表达发生改变。越来越多的实验证据表明，SNAT5 在几种类型的癌细胞中过度表达。此外，最近发表的结果表明，基质细胞中的 SNAT5 表达可以支持天冬酰胺营养缺陷型肿瘤肿瘤微环境中发生的代谢交换。我们综述了 SNAT5 转运体在生理病理学中的功能作用，并提出由于其独特的操作和调节特征，当在谷氨酰胺营养缺陷型肿瘤的肿瘤细胞或基质细胞中表达时，SNAT5 可能发挥重要的促癌作用。该转运体/SNAT5 提供谷氨酰胺、天冬酰胺和丝氨酸的净内流或外流。这些氨基酸在几种情况下具有特殊的代谢相关性。在选定类型的人类癌症中，已经描述了转运体表达或活性的变化，其中 SNAT5 可以介导肿瘤和基质细胞之间的氨基酸交换，从而提供了一个潜在的治疗靶点。这是第一篇综述总结了该转运体在生理和病理中的特征和作用。
