Affiliations
- 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- 2Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, P.R. China.
- 3Genome Institute of Singapore, Agency for Science Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore, Singapore.
- 4School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
- 5Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore.
- 6Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Electronic address: polly_chen@nus.edu.sg.
Abstract
ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
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- PMID: 38935501 DOI: 10.1016/j.celrep.2024.114400