Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, Komturstrasse 3a, 60528, Frankfurt am Main, Germany.
Department of Infectious Diseases/Molecular Virology, Medical Faculty, Center for Integrative Infectious Diseases Research (CIID), University of Heidelberg, 69120, Heidelberg, Germany.
Cell Death Dis. 2022 Aug 6;13(8):684. doi: 10.1038/s41419-022-05124-w.
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.
模式识别受体（PRRs）和干扰素（IFNs）是对抗 SARS-CoV-2 的重要抗病毒防御机制，SARS-CoV-2 是 COVID-19 大流行的病原体。III 型干扰素（IFN-λ）在自身炎症、肿瘤发生和抗病毒防御中具有细胞类型特异性和持久功能。在这里，我们确定去泛素化酶 USP22 是人类肠道上皮细胞（hIECs）中基础 IFN-λ 分泌和 SARS-CoV-2 感染的中央调节因子。USP22 缺陷的 hIECs 强烈地上调参与 IFN 信号和病毒防御的基因，包括许多 IFN 刺激基因（ISGs），IFN-λ 的分泌增加，STAT1 信号增强，即使在没有外源性 IFN 或病毒感染的情况下也是如此。有趣的是，USP22 控制基础和 2'3'-cGAMP 诱导的 STING 激活，而 STING 的缺失逆转了 STAT 激活和 ISG 和 IFN-λ 的表达。有趣的是，USP22 缺陷的 hIECs 以 STING 依赖的方式免受 SARS-CoV-2 感染、病毒复制和新形成的感染性颗粒的影响。这些发现揭示了 USP22 是 STING 和 III 型 IFN 信号的中央宿主调节剂，对 SARS-CoV-2 感染和抗病毒防御具有重要意义。
