Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality [RIP-seq]

ABSTRACT: The mechanisms that balance a robust antiviral defense with tissue tolerance at the maternal-fetal interface under physiological conditions remain largely unknown. Here, we delineate that Adar1, an A-to-I dsRNA editor, fine-tunes endogenous integrated stress response (ISR) induced by aberrant IFN signaling in the placenta. We demonstrate that placental defects caused by both fetal and placental Adar1 deletions account for embryonic lethality. Selective Adar1 deletion in the placenta (Adar1PKO) hindered the differentiation of Ifn hyper-responsive junctional zone progenitors and impaired morphogenesis and functions of the junctional zone (JZ), ultimately leading to embryonic death. Furthermore, the Adar1PKO placental Ifn hyper-response was positively amplified through the accumulation of dsRNA derived from the 3′UTR of interferon-stimulated genes (ISG-3′UTR-dsRNA). The resulting embryonic lethality was fully rescued by concurrent deletion of Mavs, Ifnar1, or Pkr, but not Zbp1 or other cell death effectors. Notably, blocking Pkr-mediated ISR alleviated JZ defects in the Adar1PKO placenta and prevented corresponding embryonic lethality. These findings demonstrate that Adar1 prevents the formation of the compartmentalized dsRNA-Mavs-Ifn-Pkr-ISR signaling axis in JZ trophoblasts by restricting ISG-3′UTR-dsRNA accumulation, shedding light on a potential therapeutic strategy targeting the ISR during pregnancy.

ORGANISM(S): Mus musculus

PROVIDER: GSE279352 | GEO | 2024/10/13

REPOSITORIES: GEO