Arppo Antti, Barker Harlan, Parkkila Seppo
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Clinical Chemistry, Fimlab Laboratories PLC, Tampere University Hospital, Tampere, Finland.
PLoS One. 2024 Dec 11;19(12):e0307731. doi: 10.1371/journal.pone.0307731. eCollection 2024.
Research on SARS-CoV-2, the viral pathogen that causes COVID-19, has identified angiotensin converting enzyme 2 (ACE2) as the primary viral receptor. Several genes that encode viral cofactors, such as TMPRSS2, NRP1, CTSL, and possibly KIM1, have since been discovered. Glutamyl aminopeptidase (APA), encoded by the gene ENPEP, is another cofactor candidate due to similarities in its biological role and high correlation with ACE2 and other human coronavirus receptors, such as aminopeptidase N (APN) and dipeptidyl peptidase 4 (DPP4). Recent studies have proposed a role for ENPEP as a viral receptor in humans, and ENPEP and ACE2 are both closely involved in the renin-angiotensin-aldosterone system proposed to play an important role in SARS-CoV-2 pathophysiology. We performed bioinformatic analyses using publicly available bulk (>17,000 samples from 49 distinct tissues) and single-cell (>2.5 million cells) RNA-Seq gene expression datasets to evaluate the expression and function of the ENPEP gene. We also investigated age- and sex-related changes in ENPEP expression. Overall, expression of ENPEP was highest in the small intestine enterocyte brush border and the kidney cortex. ENPEP is widely expressed in a subset of vascular smooth muscle cells (likely pericytes) in systemic vasculature, the heart, and the brain. ENPEP is expressed at low levels in the lower respiratory epithelium. In the lung, ENPEP is most highly expressed in para-alveolar fibroblasts. Single-cell data revealed ENPEP expression in a substantial fraction of ependymal cells, a finding not reported before in humans. Age increases ENPEP expression in skeletal muscle and the prostate, while decreasing it in the heart and aorta. Angiogenesis was found to be a central biological function associated with the ENPEP gene. Tissue-specific roles, such as protein digestion and fat metabolism, were also identified in the intestine. In the liver, the gene is linked to the complement system, a connection that has not yet been thoroughly investigated. Expression of ENPEP and ACE2 is strongly correlated in the small intestine and renal cortex. Both overall and in blood vessels, ENPEP and ACE2 have a stronger correlation than many other genes associated with SARS-CoV-2, such as TMPRSS2, CTSL, and NRP1. Possible interaction between glutamyl aminopeptidase and SARS-CoV-2 should be investigated experimentally.
对导致新冠肺炎的病毒病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的研究已确定血管紧张素转换酶2（ACE2）为主要病毒受体。此后，还发现了几个编码病毒辅助因子的基因，如跨膜丝氨酸蛋白酶2（TMPRSS2）、神经纤毛蛋白1（NRP1）、组织蛋白酶L（CTSL）以及可能的肾损伤分子1（KIM1）。由ENPEP基因编码的谷氨酰氨肽酶（APA）是另一个辅助因子候选者，因为其生物学作用具有相似性，且与ACE2以及其他人类冠状病毒受体，如氨肽酶N（APN）和二肽基肽酶4（DPP4）高度相关。最近的研究提出ENPEP在人类中作为病毒受体的作用，并且ENPEP和ACE2都密切参与肾素-血管紧张素-醛固酮系统，该系统在SARS-CoV-2病理生理学中被认为起重要作用。我们使用公开可用的批量（来自49个不同组织的>17,000个样本）和单细胞（>250万个细胞）RNA测序基因表达数据集进行生物信息学分析，以评估ENPEP基因的表达和功能。我们还研究了ENPEP表达的年龄和性别相关变化。总体而言，ENPEP在小肠肠上皮细胞刷状缘和肾皮质中表达最高。ENPEP在全身血管系统中的一部分血管平滑肌细胞（可能是周细胞）、心脏和大脑中广泛表达。ENPEP在下呼吸道上皮中的表达水平较低。在肺中，ENPEP在肺泡旁成纤维细胞中表达最高。单细胞数据显示ENPEP在相当一部分室管膜细胞中表达，这一发现此前在人类中未被报道。年龄增加会使骨骼肌和前列腺中的ENPEP表达增加，而使心脏和主动脉中的ENPEP表达降低。血管生成被发现是与ENPEP基因相关的核心生物学功能。在肠道中还确定了组织特异性作用，如蛋白质消化和脂肪代谢。在肝脏中，该基因与补体系统相关联，这一联系尚未得到充分研究。ENPEP和ACE2在小肠和肾皮质中的表达高度相关。总体而言以及在血管中，ENPEP和ACE2的相关性比许多其他与SARS-CoV-2相关的基因，如TMPRSS2、CTSL和NRP1更强。谷氨酰氨肽酶与SARS-CoV-2之间可能的相互作用应通过实验进行研究。
