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Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner [1]

ABSTRACT: Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact.

ORGANISM(S): Mus musculus

PROVIDER: GSE211208 | GEO | 2022/08/18

REPOSITORIES: GEO

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Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner [2]

Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact.

2022-08-18 | GSE211209 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner II

Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact. Peritoneal macrophages from mutant and control mice were isolated by FACS. Total RNA was subjected to next generation mRNA sequencing.

2022-10-10 | GSE214712 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner I

2022-10-10 | GSE214711 | GEO

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [WT HEK293T and mutant MDA5]

Project description:Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral double-stranded RNA (dsRNA) sensor that induces antiviral immune response. We here demonstrate that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNA because its filament formation on dsRNA is impaired by the imperfect duplex structure, AGS-variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNA. Moreover, we identified an unexpected role of RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context-dependence of self vs. non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 to recognize dsRNA comes at a cost of self-recognition, and implicates a unique role of Alu RNAs as virus-like elements that shape the primate immune system.

2018-01-29 | GSE103539 | GEO

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [ADAR1KO HEK293T and WT MDA5]

2018-01-29 | GSE104864 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-08-18 | GSE211211 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner (Set II)

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-10 | GSE214713 | GEO

RNA-Seq of FBXO44 knockdown in MDA-MB-231

Project description:Targeting FBXO44 or SUV39H1 transcriptionally reactivates repetitive elements, triggering RIG-I-MDA5-MAVS and cGAS-STING antiviral defense responses and IFN signaling, specifically in cancer cells

2021-03-26 | GSE139974 | GEO

ADAR1 utilizes independent mechanisms to suppress MDA5 and PKR activation by cellular double-stranded RNA

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.

2023-10-03 | GSE198386 | GEO

SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA

Project description:Recognition of pathogen-derived foreign nucleic acids is central to innate immune defense. This requires discrimination between structurally highly similar self and nonself nucleic acids to avoid aberrant inflammatory responses as in the autoinflammatory disorder Aicardi-Goutires syndrome (AGS). How vast amounts of self RNA are shielded from immune recognition to prevent autoinflammation is not fully understood. Here we show that SAM domain and HD domain-containing protein 1 (SAMHD1), one of the AGS-causing genes, functions as a single-stranded RNA (ssRNA) 3«exonuclease, the lack of which causes cellular RNA accumulation. Increased ssRNA in cells leads to dissolution of RNA-protein condensates, which sequester immunogenic double-stranded RNA (dsRNA). Release of sequestered dsRNA from condensates triggers activation of antiviral type I interferon via retinoic acid-inducible gene I-like receptors. Our results establish SAMHD1 as a key regulator of cellular RNA homeostasis and demonstrate that buffering of immunogenic self RNA by condensates regulates innate immune responses.

2023-02-06 | PXD035182 | Pride

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