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

Area of Science:

• Virology
• Molecular Biology
• Epigenetics

Background:

• Understanding host factors is crucial for identifying coronavirus pathogenesis mechanisms and therapeutic targets.
• Histone demethylase KDM6A's role in coronavirus infection is not fully understood.

Purpose of the Study:

• To investigate the role of KDM6A in the infection mechanisms of various coronaviruses.
• To identify the molecular pathways and protein complexes involved in KDM6A-mediated coronavirus susceptibility.
• To explore the potential of targeting the KDM6A complex as a pan-coronavirus therapeutic strategy.

Main Methods:

• Assessing KDM6A's impact on infection by SARS-CoV, SARS-CoV-2, MERS-CoV, and MHV.
• Investigating KDM6A's interaction with KMT2D and p300 using mechanistic studies.
• Analyzing the KDM6A-KMT2D-p300 complex's localization to viral receptor enhancers (e.g., ACE2).
• Evaluating the efficacy of p300 inhibition on viral receptor expression and infection resistance.

Main Results:

• KDM6A promotes infection by diverse coronaviruses independently of its demethylase activity.
• KDM6A regulates the expression of multiple coronavirus receptors, including ACE2, DPP4, and Ceacam1.
• The KDM6A-KMT2D-p300 complex is essential for regulating ACE2 expression.
• Small molecule inhibition of p300 abrogates ACE2 and DPP4 expression, conferring resistance to SARS-CoV-2 variants and MERS-CoV.

Conclusions:

• The KDM6A-KMT2D-p300 complex plays a critical role in conferring susceptibility to diverse coronaviruses.
• Targeting this complex, particularly p300 activity, presents a promising pan-coronavirus therapeutic approach.
• This discovery opens avenues for developing broad-spectrum antiviral therapies against current and emerging coronaviruses.