| First Author | Song J | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 7096 |
| PubMed ID | 36402769 | Mgi Jnum | J:331387 |
| Mgi Id | MGI:7387675 | Doi | 10.1038/s41467-022-34885-3 |
| Citation | Song J, et al. (2022) Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling. Nat Commun 13(1):7096 |
| abstractText | 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-i(fs/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. |
