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

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.

A Comprehensive Integrated Analysis of DDX3X Expression, Prognostic Value and Potential Implications for Pan-Cancer Immunity

“…DDX3X is a category of proteins in TME accompanying superior endeavor in protein phosphorylation, nuclear spots, and transcriptional coactivators, mainly related to DNA transcription, and its abnormal expression will cause chromosomes to approach misfolded or even rearranged during transcription, generating rational deoxyribonucleic acid mutations and oncogene activating [23] and inhibited of platinum resistance in ovarian cancers via lncRNA RMRP/DDX3X/PHGDH [24]. DDX3X is contributing to a variety of malignant tumors to a degree of lung malignancy [25], prostate malignancy [26, 27], breast malignancy [28], and colorectal malignancy [29], whatever is related to DDX3X recruiting supporting-in ammatory cells and leaking TME in ammatory cytokines to advance carcinoma development. DDX3X is likewise a persuasive resource to eradicate malignancy stem cells (CSCs) [12], DDX3X overexpression induces ERα phosphorylation in breast epithelial cells [30]; DDX3X advocates the G1/S cycle conversion of medulloblastoma cells and induces oral squamous cells by combining accompanying unusual activating of ATK/mTOR pathway by KRT17, all of that generates the malignant proliferation of normal cells [31], DDX3X can also embark on the RNA metabolic modi cation process [32], bind to proteins to promote distant carcinoma metastasis, and evade immune attack.…”

Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis

“…After passed through filters, lamina propria lymphocytes were enriched through 40/80% Percoll (GE Healthcare) gradient centrifugation. [38][39] For isolation of liver infiltrating immune cells, murine liver was collected and cut into 1 mm 3 pieces. After passed through filters, immune cells were enriched through density gradient centrifugation by Mouse Lymphocyte Separation Medium (DAKEWE, 7211011).…”

The Deubiquitinase OTUD1 Suppresses Secretory Neutrophil Polarization And Ameliorates Immunopathology of Periodontitis

“…Periodontitis induction on the transplanted mice were performed after 2 months to ensure that bone marrow reconstitution had occurred. [33] Co-Immunoprecipitation and Immunoblot Analysis: HEK293T cells were transfected with the indicated plasmids and lysed by lysis buffer containing 10% (v/v) glycerol, 0.5% (v/v) NP-40, 150 mM NaCl, and 0.1 mM EDTA with protease inhibitor cocktail (Roche). Cell lysates were incubated with anti-FLAG antibody (Sigma, F3165) and protein A/G (Santa Cruz Biotechnology, sc-2003).…”

“…Periodontitis induction on the transplanted mice were performed after 2 months to ensure that bone marrow reconstitution had occurred. [ 33 ]…”