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

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.Author summary: Three highly pathogenic coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 have spilled over into the human population in the last two decades. It is important to determine the mechanisms underlying how these viruses cause infection in order to increase our understanding of how viruses cause disease and to aid in the development of new therapeutics against current and future coronaviruses. Here we identify that the host proteins KDM6A, KMT2D, and p300 are critical for coronavirus infection. KDM6A, KMT2D, and p300 are important proteins implicated in cancer and developmental syndromes. They modify histone proteins, which regulate expression of specific host genes. We show that the KDM6A-KMT2D-p300 axis turns on expression of the host genes ACE2 and DPP4, which encode the receptors for SARS-like coronaviruses and MERS-CoV, respectively. KDM6A, KMT2D, and p300 act on the enhancer regions of the coronavirus receptor genes to turn on receptor expression. Small molecule inhibitors of p300 activity block receptor expression in both cell lines and primary human airway cells. This inhibition is well tolerated and makes the cells resistant to infection. This highlights the potential for targeting the KDM6A-KMT2D-p300 axis for diverse coronavirus infections.