Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Commun Biol. 2022 Jul 1;5(1):651. doi: 10.1038/s42003-022-03609-0.
Angiotensin-converting enzyme 2 (ACE2) has been identified as a primary receptor for severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2). Here, we investigated the expression regulation of ACE2 in enterocytes under amino acid deprivation conditions. In this study, we found that ACE2 expression was upregulated upon all or single essential amino acid deprivation in human colonic epithelial CCD841 cells. Furthermore, we found that knockdown of general control nonderepressible 2 (GCN2) reduced intestinal ACE2 mRNA and protein levels in vitro and in vivo. Consistently, we revealed two GCN2 inhibitors, GCN2iB and GCN2-IN-1, downregulated ACE2 protein expression in CCD841 cells. Moreover, we found that increased ACE2 expression in response to leucine deprivation was GCN2 dependent. Through RNA-sequencing analysis, we identified two transcription factors, MAFB and MAFF, positively regulated ACE2 expression under leucine deprivation in CCD841 cells. These findings demonstrate that amino acid deficiency increases ACE2 expression and thereby likely aggravates intestinal SARS-CoV-2 infection.
血管紧张素转化酶 2（ACE2）已被鉴定为严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）的主要受体。在这里，我们研究了氨基酸剥夺条件下肠细胞中 ACE2 的表达调控。在这项研究中，我们发现人结肠上皮 CCD841 细胞在全部或单个必需氨基酸剥夺时 ACE2 表达上调。此外，我们发现，普遍控制不可抑制 2（GCN2）的敲低减少了体外和体内的肠 ACE2 mRNA 和蛋白水平。一致地，我们揭示了两种 GCN2 抑制剂，GCN2iB 和 GCN2-IN-1，下调了 CCD841 细胞中的 ACE2 蛋白表达。此外，我们发现，亮氨酸剥夺引起的 ACE2 表达增加依赖于 GCN2。通过 RNA 测序分析，我们鉴定了两种转录因子，MAFB 和 MAFF，在 CCD841 细胞中，亮氨酸缺乏时正向调节 ACE2 的表达。这些发现表明，氨基酸缺乏增加 ACE2 的表达，从而可能加重肠道 SARS-CoV-2 感染。
