XAF1 Protects Host Against RNA Viruses by Stabilizing IRF1-Dependent Antiviral Immunity

Background: XIAP-associated factor 1 (XAF1) is an interferon (IFN)-stimulated gene (ISG) that enhances IFN-induced apoptosis. However, it is unexplored whether XAF1 is essential for host fighting against viruses. Herein, we have dissected the role of XAF1 in cells and mice infected with different RNA viruses. Methods: The function of XAF1 in vitro was determined by overexpression, knockdown, and knockout of XAF1 in A549 cell lines, primary human PBMC, and mouse macrophages. XAF1 role in vivo was assessed using WT and Xaf1 -/- mice infected with PR8 or VSV. Findings: XAF1 is significantly upregulated during host infected with different RNA viruses. IFN regulatory factor 1 (IRF1) determines the induction of XAF1 during antiviral immunity. Overexpression of XAF1 protects host cells against various RNA viruses independent of apoptosis. Knockout of XAF1 attenuates host antiviral innate immunity in vitro and in vivo , which leads to more severe lung injuries and higher mortality in the influenza infection mouse model. XAF1 stabilizes IRF1 protein by antagonizing the CHIP-mediated degradation of IRF1, and thus induces more antiviral IRF1 target genes including DDX58, DDX60, MX1, and OAS2.Interpretation: Our study has described a protective role of XAF1 in host antiviral innate immunity against RNA viruses. We have also elucidated the molecular mechanism that IRF1 and XAF1 form a positive feedback loop to induce rapid and robust antiviral immunity. Funding This work was mainly supported by the National Key Research and Development Program of China (2018YFA0900803) and Natural Science Foundation of Jiangsu Province (BK20200004 and BK20210118).Declaration of Interest: The authors declare that no conflict of interests exist. Ethical Approval: All animal experiments were conducted according to the US National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Animal Service Center of ISM (ISM-IACUC-0011-R).