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| Status |
Public on Feb 26, 2021 |
| Title |
Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity [A33_OE_RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP syn- thase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflamma- tion in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
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| Overall design |
Transcript profiles of wildtype (WT) or Slc25a33-MycFlag overexpressing HeLa cells treated with 40 µM 2',3' dideoxycytidine (ddC) for 72 h.
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| Contributor(s) |
Sprenger H, MacVicar T, Altmüller J |
| Citation(s) |
33903774 |
| |
| Submission date |
Nov 18, 2020 |
| Last update date |
May 28, 2021 |
| Contact name |
Thomas MacVicar |
| E-mail(s) |
tmacvicar@age.mpg.de
|
| Organization name |
Max Planck Institute for Biology of Ageing
|
| Street address |
Joseph-Stelzmann Str 9B
|
| City |
Cologne |
| ZIP/Postal code |
50931 |
| Country |
Germany |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE161736 |
Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity |
|
| Relations |
| BioProject |
PRJNA679269 |
| SRA |
SRP293107 |
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