Genomics

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


ABSTRACT: 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. Overall design: cytoplasmic RNA profiles of a footprinting assay were generated in duplicate using Illumina Miseq V2.

INSTRUMENT(S): Illumina MiSeq (Homo sapiens)

SUBMITTER: Sun Hur 

PROVIDER: GSE104864 | GEO | 2018-01-29

REPOSITORIES: GEO

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Publications

Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation.

Ahmad Sadeem S   Mu Xin X   Yang Fei F   Greenwald Emily E   Park Ji Woo JW   Jacob Etai E   Zhang Cheng-Zhong CZ   Hur Sun S  

Cell 20180125 4


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 dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here 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-dsRNAs because of its  ...[more]

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