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| Status |
Public on Dec 03, 2014 |
| Title |
Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
RNA sequencing of wild-type or Interferon Alpha receptor 1 Knockout MEF cells treated with DMSO or the Caspase Inhibitor Q-VD-OPh.
The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify of a mechanism by which mitochondria and downstream pro-apoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response, and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a pro-inflammatory type of cell death.
In order to determine whether the pharmacological inhibition of caspases could activate the type I interferon response, we treated WT MEFs with the caspase inhibitor Q-VD-OPH. The inhibitor induced an increased expression of ISGs, which was dependent on type I IFN receptor (IFNAR1) signaling.
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| Overall design |
RNA was extracted from duplicate samples and libraries generated for sequencing using the directional RNA-Seq library prep at the Yale Center for Genome Analysis. Libraries were sequenced using a Hiseq2500 sequencer to generate 76bp single-end reads. Duplicate samples were analyzed for each condition.
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| Contributor(s) |
Flavell RA, Rongvaux A, Harman CC |
| Citation(s) |
25525875 |
| Submission date |
Dec 02, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Christian Harman |
| Organization name |
Yale University
|
| Department |
Genetics/Immunobiology
|
| Lab |
Flavell Lab
|
| Street address |
300 Cedar Street, The Anlyan Center
|
| City |
New Haven |
| State/province |
Connecticut |
| ZIP/Postal code |
06520 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA269079 |
| SRA |
SRP050448 |
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