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Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [RIPseq]

ABSTRACT: Acute loss of INT induces transcription factors that initiate stress-responses like the Integrated Stress Response (ISR). Inefficient elongation upon INT loss enables termination in introns and dsRNA formation. dsRNA is recognized by PKR, which persistently activates the ISR in samples from patients with INT mutations

ORGANISM(S): Homo sapiens

PROVIDER: GSE267044 | GEO | 2025/04/16

REPOSITORIES: GEO

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Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [48h_INTS8_RNAseq]

Project description:Acute loss of INT induces transcription factors that initiate stress-responses like the Integrated Stress Response (ISR). Inefficient elongation upon INT loss enables termination in introns and dsRNA formation. dsRNA is recognized by PKR, which persistently activates the ISR in samples from patients with INT mutations

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Double-stranded RNA triggers a distinct integrated stress response in the early embryo [cas9 tol2]

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Project description:The antiviral defense in vertebrates requires the innate immune system to sense foreign “non-self” nucleic acids while avoiding “self” nucleic acids, which is accomplished by an intricate system. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA editing enzyme ADAR1 to prevent their dsRNA structure pattern from being recognized as viral dsRNA. Lack of RNA editing by ADAR1 enables activation of MDA5, a cytosolic dsRNA sensor, by cellular dsRNA. Additional RNA editing- independent functions of ADAR1 have been proposed, but the specific mechanism remains elusive. Here we demonstrate that RNA binding by ADAR1, independent of its editing activity, restricts the activation of PKR, another cytosolic dsRNA sensor, by cellular dsRNA. Mechanistically, the loss of ADAR1 editing caused MDA5 activation to induce interferon signaling, while a lack of ADAR1 protein or its dsRNA binding ability led to PKR activation, with subsequent stress granule formation and proliferation arrest. Based on these findings we rescued the Adar1−/− mice from embryonic lethality to adulthood by deleting both MDA5 and PKR, in contrast to the limited rescue of Adar1−/− mice by removing MDA5 or PKR alone. Our findings reveal a multifaceted contribution of ADAR1 in regulating the immunogenicity of “self” dsRNAs. Furthermore, ADAR1 is an immuno-oncology target for drug development, and the separation of ADAR1’s RNA editing and binding functions provides mechanistic insights for such developments.

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Project description:Protein kinase R (PKR), an innate immune sensor for double-stranded RNA (dsRNA), is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a crucial and controversial role in the PKR pathway. We demonstrate that PACT is an essential negative regulator of PKR against endogenous dsRNA ligands like inverted repeat Alu RNAs, which satisfy PKR’s selectivity for long dsRNA and robustly activate PKR in the absence of PACT. PACT employs an unusual inhibitory mechanism sensitive to dsRNA length and concentration, inhibiting PKR through low-affinity interactions most effective when both are bound to the same dsRNA molecule. Consequently, PACT’s inhibition of PKR is more robust when dsRNA is longer and less abundant, with minimal effect on abundant or short dsRNA. Thus, PACT functions as a rheostat, setting the PKR activation threshold for long endogenous dsRNA without altering its inherent activity.

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