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| Status |
Public on Jan 29, 2018 |
| Title |
Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [WT HEK293T and mutant MDA5] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
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.
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| Overall design |
cytoplasmic RNA profiles of a footprinting assay were generated in duplicate using Illumina Miseq V2.
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| Contributor(s) |
Ahmad S, Hur S, Mu X, Yang F, Greenwald E, Park JW, Jacob E, Zhang C |
| Citation(s) |
29395326 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AI106912 |
Molecular Mechanisms for Antiviral Signal Activation by MDA5 and RIG-I |
CHILDREN'S HOSPITAL |
Sun Hur |
| R01 AI111784 |
Structural and functional analyses of the RIG-I filament in innate immunity |
CHILDREN'S HOSPITAL |
Sun Hur |
| R21 AI130791 |
Re-defining RIG-I-like helicases as viral RNA receptors with effector functions |
CHILDREN'S HOSPITAL |
Sun Hur |
|
| Submission date |
Sep 06, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Sun Hur |
| Organization name |
Boston Children's Hospital
|
| Department |
Program in Cellular and Molecular Medicine (PCMM)
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| Lab |
Hur
|
| Street address |
3 Blackfan Circle, Boston, MA, 02115
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
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| Samples (5)
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| This SubSeries is part of SuperSeries: |
| GSE104865 |
Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation |
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| Relations |
| BioProject |
PRJNA401809 |
| SRA |
SRP117067 |
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