The KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression.

Autor: Wei J; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America., Alfajaro MM; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America., Cai WL; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America., Graziano VR; Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, United States of America., Strine MS; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America., Filler RB; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America., Biering SB; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America., Sarnik SA; University of Colorado Boulder, Boulder, Colorado, United States of America., Patel S; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America., Menasche BL; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America., Compton SR; Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America., Konermann S; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA.; Arc Institute, Palo Alto, California, United States of America., Hsu PD; Arc Institute, Palo Alto, California, United States of America.; Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.; Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, United States of America.; Center for Computational Biology, University of California, Berkeley, California, United States of America., Orchard RC; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America., Yan Q; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, United States of America.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, United States of America., Wilen CB; Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Jul 06; Vol. 19 (7), pp. e1011351. Date of Electronic Publication: 2023 Jul 06 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011351
Abstrakt: 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.
Competing Interests: C.B.W. and J.W. have a patent pending related to this work entitled: “Compounds and Compositions for Treating, Ameliorating, and/or Preventing SARS-CoV-2 Infection and/or Complications Thereof.” C.B.W. is a consultant for Exscientia (Oxford, UK). The other authors declare no competing interests.
(Copyright: © 2023 Wei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje