ArticleEMBO molecular medicine2022
SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19.
Article in EMBO molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 23 citations in OpenAlex.
- Inhibition of SARS-CoV-2 spike S1-ACE2 binding interaction and downregulation of ACE2 gene expression by Malaysian stingless bee honey and its bioactive compound, stilbamidine (SDC).Molecular biology reports · 2026Article
- MAP4K2 suppresses antitumor immunity in a pancreatic cancer model by promoting Treg differentiation.The Journal of clinical investigation · 2026Article
- ACE2: Friend or Foe in Post-COVID-19 Neurodegeneration?International journal of molecular sciences · 2025Review
- Molecular dissection of the role of ACE2 in glucose homeostasis.Physiological reviews · 2025Review
- Longitudinal Assessment of Nasopharyngeal Biomarkers Post-COVID-19: Unveiling Persistent Markers and Severity Correlations.Journal of proteome research · 2024Article
- Human E3 ubiquitin ligases: accelerators and brakes for SARS-CoV-2 infection.Biochemical Society transactions · 2024Review
- Angiotensin-Converting Enzyme 2 Posttranslational Modifications and Implications for Hypertension and SARS-CoV-2: 2023 Lewis K. Dahl Memorial Lecture.Hypertension (Dallas, Tex. : 1979) · 2024Review
- Multiple E3 ligases act as antiviral factors against SARS-CoV-2 via inducing the ubiquitination and degradation of ORF9b.Journal of virology · 2024Article
- Article
- The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling.Nature communications · 2024Article
- DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α.The Journal of clinical investigation · 2023Article
- ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification.Journal of biomedical science · 2023Review
- SARS-CoV-2 spike protein reduces burst activities in neurons measured by micro-electrode arrays.Annals of medicine and surgery (2012) · 2023Article
- Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2.American journal of respiratory cell and molecular biology · 2023Article
- Tipping the Balance of Ubiquitination toward a Therapy for COVID-19.American journal of respiratory cell and molecular biology · 2023Article
- Proteoglycans: a common portal for SARS-CoV-2 and extracellular vesicle uptake.American journal of physiology. Cell physiology · 2023Review
- Role of E3 ubiquitin ligases and deubiquitinating enzymes in SARS-CoV-2 infection.Frontiers in cellular and infection microbiology · 2023Review
- SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19.EMBO molecular medicine · 2022Article
- Application of the humanized mouse model in research into SARS-CoV-2 infection (Review).Medicine internationalReview
Corrections and comments
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Authors and funding
8 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells was correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein-stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to the dissociation of ACE2 from its E3 ligase UBR4. Reduction in UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, and ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
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