Alkhofash Nesreen F, Ali Bassam R
Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al-Ain, United Arab Emirates.
Front Cell Dev Biol. 2025 Aug 7;13:1589534. doi: 10.3389/fcell.2025.1589534. eCollection 2025.
The interaction between angiotensin-converting enzyme 2 (ACE2) and the sodium-dependent Broad neutral Amino acid Transporter 1 (B0AT1), encoded by the gene, is increasingly recognized as pivotal in both physiological and pathological contexts. B0AT1 facilitates neutral amino acid transport and nutrient absorption, while ACE2 regulates vascular homeostasis and inflammation through the renin-angiotensin system. Mutations in are implicated in Hartnup disease, a metabolic disorder characterized by defective amino acid transport. However, the cellular mechanisms underlying Hartnup disease-causing mutations' impact on B0AT1 and ACE2 function remain unclear.
This study evaluated the subcellular localization and trafficking of 18 Hartnup disease-causing B0AT1 variants using experimental approaches including biochemical assays and In Silico analysis. The impact of these variants on ACE2 trafficking and plasma membrane targeting was also assessed to elucidate their interplay.
Nine B0AT1 variants (R57C, G93R, R95P, R178Q, L242P, G284R, S303L, D517G, P579L) were found to be retained in the endoplasmic reticulum, impairing their trafficking to the plasma membrane. These variants were distributed across multiple B0AT1 structural domains. Importantly, several of these ER-retained variants, particularly R178Q and S303L, significantly disrupted ACE2 intracellular trafficking and its localization to the plasma membrane, indicating a direct effect on ACE2 subcellular targeting.
The findings reveal that Hartnup disease-causing mutations can lead to ER retention of B0AT1, which in turn has a variable effect on ACE2 trafficking. This disruption likely contributes to Hartnup disease pathogenesis by impairing amino acid transport and may influence ACE2-mediated physiological functions beyond the renin-angiotensin system. Understanding these molecular mechanisms enhances insight into ACE2-B0AT1 interactions and could inform future therapeutic strategies and biomarker development for related disorders. Further research is needed to explore these pathways and their implications in disease.
血管紧张素转换酶2（ACE2）与由该基因编码的钠依赖性中性氨基酸转运体1（B0AT1）之间的相互作用，在生理和病理环境中都日益被认为是关键的。B0AT1促进中性氨基酸转运和营养吸收，而ACE2通过肾素 - 血管紧张素系统调节血管稳态和炎症。该基因的突变与哈特纳普病有关，这是一种以氨基酸转运缺陷为特征的代谢紊乱疾病。然而，导致哈特纳普病的突变影响B0AT1和ACE2功能的细胞机制仍不清楚。
本研究使用包括生化分析和计算机模拟分析在内的实验方法，评估了18种导致哈特纳普病的B0AT1变体的亚细胞定位和转运。还评估了这些变体对ACE2转运和质膜靶向的影响，以阐明它们之间的相互作用。
发现9种B0AT1变体（R57C、G93R、R95P、R178Q、L242P、G284R、S303L、D517G、P579L）滞留在内质网中，损害了它们向质膜的转运。这些变体分布在多个B0AT1结构域中。重要的是，这些内质网滞留变体中的几个，特别是R178Q和S303L，显著破坏了ACE2的细胞内转运及其在质膜上的定位，表明对ACE2亚细胞靶向有直接影响。
研究结果表明，导致哈特纳普病的突变可导致B0AT1在内质网滞留，进而对ACE2转运产生不同影响。这种破坏可能通过损害氨基酸转运导致哈特纳普病发病机制，并可能影响肾素 - 血管紧张素系统以外的ACE2介导的生理功能。了解这些分子机制有助于深入了解ACE2 - B0AT1相互作用，并可为未来相关疾病的治疗策略和生物标志物开发提供信息。需要进一步研究来探索这些途径及其在疾病中的意义。
