It has been reported that SARS-CoV-2 may use ACE2 as a receptor to gain entry into human cells, in a way similar to that of SARS-CoV. Analyzing the distribution and expression level of ACE2 may therefore help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we utilized previously uploaded information on ACE2 expression in various conditions including SARS-CoA to evaluate the role of ACE2 in SARS-CoV and extrapolate that to COVID-19. We found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different. However, based on the elevated expression of ACE2 in cigarette smokers, we speculate that long-term smoking may be a risk factor for COVID-19. Analysis of ACE2 in SARS-CoV infected cells suggests that ACE2 is not only a receptor but is also involved in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may help clinicians and researchers gain more insight into the pathogenesis of SARS-CoV-2 and design therapeutic strategies for COVID-19.
The 2019-nCoV is reported to share the same entry (ACE2) as SARS-CoV according to the updated findings. Analyzing the distribution and expression level of the route of coronavirus may help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different, suggesting relatively similar susceptibility. Besides, based on the expression of ACE2 in smoking individuals, we inferred that long-term smoking might be a risk factor for 2019-nCoV. Analyzing the ACE2 in SARS-CoV infected cells suggested that ACE2 was more than just a receptor but also participated in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we also constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may explain the clinical symptoms so far and help clinicians and researchers understand the pathogenesis and design therapeutic strategies for 2019-nCoV. : medRxiv preprint GO biological process annotation gmt file was downloaded from MSigDB (https://www.gsea-msigdb.org/gsea/msigdb/). GSEA was performed to analyze the possible biological processes related to ACE2 in healthy people using clusterProfiler (12). The parameters were nPerm = 1000, minGSSize = 10, maxGSSize = 500, the biological processes with p-value < 0.05 were considered significant. GSVA was performed using GSVA R package. The immune infiltrating was quantified using the ssGSEA method in GSVA R package. The gene list for immune cells was derived from Bindea G et al.(13). PPIAll viral-related biological process and cytokine secretion-biological process proteins were extracted from the gmt file, Cytoscape v3.7.2 was used to construct the PPI network using BisoGenet application, the PPI sources include DIP, BIOGRID, HPRD, INTACT, MINT and BIND. And the nodes with topological importance in the interaction network were screened by calculating Degree Centrality (DC) with the Cytoscape plugin CytoNCA. Hub proteins were identified using Cytoscape plugin CytoHubba.
Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. However, the mechanism of neuritin in modulating neurite growth has not been elucidated. Here, using yeast two-hybrid we screened and discovered the interaction of neuritin and neuralized (NEURL1), which is an important regulator that can activate Notch signaling through promoting endocytosis of Notch ligand. And then we identified the interaction of neuritin and neuralized by co-immunoprecipitation (IP) assays, and clarified that neuritin and NEURL1 were co-localized on the cell membrane of SH-SY5Y cells. Moreover, neuritin significantly suppressed Notch ligand Jagged1 (JAG1) endocytosis promoted by NEURL1, and then inhibited the activation of Notch receptor Notch intracellular domain (NICD) and decreased the expression of downstream gene hairy and enhancer of split-1 (HES1). Importantly, the effect of neuritin on inhibiting Notch signaling was rescued by NEURL1, which indicated that neuritin is an upstream and negative regulator of NEURL1 to inhibit Notch signaling through interaction with NEURL1. Notably, recombinant neuritin restored the retraction of neurites caused by activation of Notch, and neurite growth stimulated by neuritin was partially blocked by NEURL1. These findings establish neuritin as an upstream and negative regulator of NEURL1 that inhibits Notch signaling to promote neurite growth. This mechanism connects neuritin with Notch signaling, and provides a valuable foundation for further investigation of neuritin’s role in neurodevelopment and neural plasticity.
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