Reciprocal regulation of RIG-I and XRCC4 connects DNA repair with RIG-I immune signaling.

Autor: Guo G; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Gao M; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Gao X; Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., Zhu B; Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., Huang J; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Tu X; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Kim W; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Zhao F; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Zhou Q; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Zhu S; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Wu Z; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Yan Y; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Zhang Y; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Zeng X; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Zhu Q; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Yin P; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Luo K; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Sun J; Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., Deng M; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. deng.min@mayo.edu.; Department of Oncology, Mayo Clinic, Rochester, MN, USA. deng.min@mayo.edu., Lou Z; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. lou.zhenkun@mayo.edu.; Department of Oncology, Mayo Clinic, Rochester, MN, USA. lou.zhenkun@mayo.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Apr 12; Vol. 12 (1), pp. 2187. Date of Electronic Publication: 2021 Apr 12.
DOI: 10.1038/s41467-021-22484-7
Abstrakt: The RNA-sensing pathway contributes to type I interferon (IFN) production induced by DNA damaging agents. However, the potential involvement of RNA sensors in DNA repair is unknown. Here, we found that retinoic acid-inducible gene I (RIG-I), a key cytosolic RNA sensor that recognizes RNA virus and initiates the MAVS-IRF3-type I IFN signaling cascade, is recruited to double-stranded breaks (DSBs) and suppresses non-homologous end joining (NHEJ). Mechanistically, RIG-I interacts with XRCC4, and the RIG-I/XRCC4 interaction impedes the formation of XRCC4/LIG4/XLF complex at DSBs. High expression of RIG-I compromises DNA repair and sensitizes cancer cells to irradiation treatment. In contrast, depletion of RIG-I renders cells resistant to irradiation in vitro and in vivo. In addition, this mechanism suggests a protective role of RIG-I in hindering retrovirus integration into the host genome by suppressing the NHEJ pathway. Reciprocally, XRCC4, while suppressed for its DNA repair function, has a critical role in RIG-I immune signaling through RIG-I interaction. XRCC4 promotes RIG-I signaling by enhancing oligomerization and ubiquitination of RIG-I, thereby suppressing RNA virus replication in host cells. In vivo, silencing XRCC4 in mouse lung promotes influenza virus replication in mice and these mice display faster body weight loss, poorer survival, and a greater degree of lung injury caused by influenza virus infection. This reciprocal regulation of RIG-I and XRCC4 reveals a new function of RIG-I in suppressing DNA repair and virus integration into the host genome, and meanwhile endues XRCC4 with a crucial role in potentiating innate immune response, thereby helping host to prevail in the battle against virus.
Databáze: MEDLINE
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