Abstract
Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto-inflammation, tumorigenesis, and antiviral defense. Here, we identify the deubiquitinating enzyme USP22 as central regulator of basal IFN-λ secretion and SARS-CoV-2 infections in human intestinal epithelial cells (hIECs). USP22-deficient hIECs strongly upregulate genes involved in IFN signaling and viral defense, including numerous IFN-stimulated genes (ISGs), with increased secretion of IFN-λ and enhanced STAT1 signaling, even in the absence of exogenous IFNs or viral infection. Interestingly, USP22 controls basal and 2’3′-cGAMP-induced STING activation and loss of STING reversed STAT activation and ISG and IFN-λ expression. Intriguingly, USP22-deficient hIECs are protected against SARS-CoV-2 infection, viral replication, and the formation of de novo infectious particles, in a STING-dependent manner. These findings reveal USP22 as central host regulator of STING and type III IFN signaling, with important implications for SARS-CoV-2 infection and antiviral defense.
【초록키워드】 SARS-CoV-2, viral infection, Antiviral, SARS-COV-2 infection, COVID-19 pandemic, interferons, IFN signaling, Pattern recognition, viral replication, Control, IFN, epithelial cells, Pattern recognition receptors, receptor, Stat1, pattern, expression, SARS-CoV-2 infections, ISGs, IFNs, STING, function, ISG, Signaling, STAT, Type III IFN, causative agent, Activation, Particles, PRRs, tumorigenesis, enzyme, interferons (IFNs), IFN-stimulated genes, secretion, basal, Defense, de novo, IFN-λ, exogenous IFN, Host, implication, Type III IFNs, USP22, identify, involved, absence, long-lasting, Type, IFN-stimulated gene, reversed, intestinal epithelial cell, interferons (IFNs, 【제목키워드】 Control, Signaling, type III interferon, Activation,