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Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104865 | GEO | 2018/01/29

REPOSITORIES: GEO

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

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 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 limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system.

| S-EPMC5807104 | biostudies-literature

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [ADAR1KO HEK293T and WT 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 | GSE104864 | 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

Project description:Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation

| PRJNA414051 | ENA

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

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

| PRJNA414057 | ENA

Widespread rearrangement of 3D chromatin organization underlies Polycomb-mediated stress-induced silencing

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-02-23 | E-GEOD-63518 | biostudies-arrayexpress

Inflammation-Driven Carcinogenesis is Mediated through STING

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-05-31 | E-GEOD-57605 | biostudies-arrayexpress

Thymic mimetic cells function beyond self-tolerance

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

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Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

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

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Classical dendritic cells are required for dietary antigen-mediated peripheral regulatory T cell and tolerance induction

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