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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

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			Action	DRS
		Other
	GSE279352_Mda5-RIP.csv.gz	Csv

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Project description:Sensing of double-stranded RNA (dsRNA) is an important component of innate immunity. Proteins like PKR and MDA5 recognize dsRNA and activate various pathways to fight viral infection. In addition to viral dsRNA, many endogenous RNAs containing double-stranded regions can be misrecognized as immunogenic. The RNA editing enzyme ADAR1, specifically its p150 isoform, has been shown to suppress activation of PKR and MDA5 through its A-to-I editing activity. While the cytoplasmic ADAR1-p150 isoform has been well established within this role, the functions of the nuclear ADAR1-p110 isoform are less understood. To address this knowledge gap, we utilized proximity labeling by APEX2 to identify putative ADAR1-p110 interacting proteins. We identified 110 proteins across three breast cancer cell lines that either interact with p110 or are within close proximity. Many of these proteins have known roles in RNA metabolism. Nine of the identified proteins belong to the DEAD or DEAH box families of RNA helicases, including DHX9. DHX9 is overexpressed in breast cancer, with expression closely correlated with that of p110. By co-immunoprecipitation we confirmed that p110 interacts with DHX9. Knockdown of DHX9 in several triple-negative breast cancer cell lines caused cell death and activation of the dsRNA sensor PKR. In two cell lines that are refractory to knockdown of ADAR1, the combined knockdown of DHX9 and ADAR1 caused a substantial increase in PKR activity, where knockdown of either alone had no effect. Knockdown of DHX9 and ADAR1 caused activation of the type I IFN pathway, RNase L and NF-KB signaling. Activation of these proteins and pathways was not seen with individual knockdown of ADAR1 or DHX9. Activation of PKR following combined knockdown of ADAR1 and DHX9 could be rescued by expression of p110, p150, DHX9, and catalytically inactive DHX9. Additionally PKR activation could be rescued by the dsRBM of DHX9, revealing an important role for dsRBMs in suppressing PKR activation. Together these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.

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

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