Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling

Jia Song, Wei Zhao, Xin Zhang, Wenyu Tian, Xuyang Zhao, Liang Ma, Yongtong Cao, Yuxin Yin (), Xuehui Zhang (), Xuliang Deng () and Dan Lu ()
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Jia Song: Peking University School and Hospital of Stomatology
Wei Zhao: China-Japan Friendship Hospital
Xin Zhang: Peking University Health Science Center
Wenyu Tian: Peking University Health Science Center
Xuyang Zhao: Peking University Health Science Center
Liang Ma: China-Japan Friendship Hospital
Yongtong Cao: China-Japan Friendship Hospital
Yuxin Yin: Peking University Health Science Center
Xuehui Zhang: Peking University School and Hospital of Stomatology
Xuliang Deng: Peking University School and Hospital of Stomatology
Dan Lu: Peking University Health Science Center

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract RIG-I/DDX58 plays a key role in host innate immunity. However, its therapeutic potential for inflammation-related cancers remains to be explored. Here we identify frameshift germline mutations of RIG-I occurring in patients with colon cancer. Accordingly, Rig-ifs/fs mice bearing a frameshift mutant Rig-i exhibit increased susceptibility to colitis-related colon cancer as well as enhanced inflammatory response to chemical, virus or bacteria. In addition to interruption of Rig-i mRNA translation, the Rig-i mutation changes the secondary structure of Rig-i pre-mRNA and impairs its association with DHX9, consequently inducing a circular RNA generation from Rig-i transcript, thereby, designated as circRIG-I. CircRIG-I is frequently upregulated in colon cancers and its upregulation predicts poor outcome of colon cancer. Mechanistically, circRIG-I interacts with DDX3X, which in turn stimulates MAVS/TRAF5/TBK1 signaling cascade, eventually activating IRF3-mediated type I IFN transcription and aggravating inflammatory damage. Reciprocally, all-trans retinoic acid acts as a DHX9 agonist, ameliorates immunopathology through suppression of circRIG-I biogenesis. Collectively, our results provide insight into mutant RIG-I action and propose a potential strategy for the treatment of colon cancer.

Date: 2022
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DOI: 10.1038/s41467-022-34885-3

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