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

Guijie Guo, Ming Gao, Xiaochen Gao, Bibo Zhu, Jinzhou Huang, Xinyi Tu, Wootae Kim, Fei Zhao, Qin Zhou, Shouhai Zhu, Zheming Wu, Yuanliang Yan, Yong Zhang, Xiangyu Zeng, Qian Zhu, Ping Yin, Kuntian Luo, Jie Sun, Min Deng () and Zhenkun Lou ()
Additional contact information
Guijie Guo: Mayo Clinic
Ming Gao: Mayo Clinic
Xiaochen Gao: Mayo Clinic College of Medicine and Science
Bibo Zhu: Mayo Clinic College of Medicine and Science
Jinzhou Huang: Mayo Clinic
Xinyi Tu: Mayo Clinic
Wootae Kim: Mayo Clinic
Fei Zhao: Mayo Clinic
Qin Zhou: Mayo Clinic
Shouhai Zhu: Mayo Clinic
Zheming Wu: Mayo Clinic
Yuanliang Yan: Mayo Clinic
Yong Zhang: Mayo Clinic
Xiangyu Zeng: Mayo Clinic
Qian Zhu: Mayo Clinic
Ping Yin: Mayo Clinic
Kuntian Luo: Mayo Clinic
Jie Sun: Mayo Clinic College of Medicine and Science
Min Deng: Mayo Clinic
Zhenkun Lou: Mayo Clinic

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22484-7

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