PLoS pathogens, 2023-07, Vol.19 (7), p.e1011351-e1011351
2023
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- Autor(en) / Beteiligte
- Titel
- The KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression
- Ist Teil von
- PLoS pathogens, 2023-07, Vol.19 (7), p.e1011351-e1011351
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2023
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Identification of host determinants of coronavirus infection informs mechanisms of pathogenesis and may provide novel therapeutic targets. Here, we demonstrate that the histone demethylase KDM6A promotes infection of diverse coronaviruses, including SARS-CoV, SARS-CoV-2, MERS-CoV and mouse hepatitis virus (MHV) in a demethylase activity-independent manner. Mechanistic studies reveal that KDM6A promotes viral entry by regulating expression of multiple coronavirus receptors, including ACE2, DPP4 and Ceacam1. Importantly, the TPR domain of KDM6A is required for recruitment of the histone methyltransferase KMT2D and histone deacetylase p300. Together this KDM6A-KMT2D-p300 complex localizes to the proximal and distal enhancers of ACE2 and regulates receptor expression. Notably, small molecule inhibition of p300 catalytic activity abrogates ACE2 and DPP4 expression and confers resistance to all major SARS-CoV-2 variants and MERS-CoV in primary human airway and intestinal epithelial cells. These data highlight the role for KDM6A-KMT2D-p300 complex activities in conferring diverse coronaviruses susceptibility and reveal a potential pan-coronavirus therapeutic target to combat current and emerging coronaviruses. One Sentence Summary: The KDM6A/KMT2D/EP300 axis promotes expression of multiple viral receptors and represents a potential drug target for diverse coronaviruses.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7374, 1553-7366eISSN: 1553-7374DOI: 10.1371/journal.ppat.1011351Titel-ID: cdi_plos_journals_2851954747
- Format
- –
- Schlagworte
- ACE2, Angiotensin-converting enzyme 2, Angiotensin-Converting Enzyme 2 - metabolism, Animals, Apoptosis, Biology and life sciences, Catalytic activity, CD66 antigen, CEACAM1 protein, Cells, Cloning, Coronaviridae, Coronaviruses, COVID-19, CRISPR, Dipeptidyl Peptidase 4 - metabolism, Disease susceptibility, Drug resistance, Epithelial cells, Epithelium, Evaluation, Health aspects, Hepatitis, Histone deacetylase, Histone Demethylases - metabolism, Histone methyltransferase, Histones, Humans, Infections, Medicine and Health Sciences, Methyltransferases, Mice, Microscopy, Middle East respiratory syndrome, Middle East Respiratory Syndrome Coronavirus - metabolism, Pathogenesis, Physical Sciences, Receptors, Receptors, Virus - genetics, Receptors, Virus - metabolism, Research and Analysis Methods, Respiratory diseases, SARS-CoV-2 - metabolism, Severe acute respiratory syndrome coronavirus 2, Therapeutic applications, Therapeutic targets, Viral diseases, Viral infections, Viruses