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YME1L1 KnockOut MEF Cells Whole Proteomics

ABSTRACT: Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remained enigmatic. We found that mtDNA-dependent immune signaling via the cGAS-STING pathway is under metabolic control and induced by cellular nucleotide deficiency. The mitochondrial protease YME1L preserves nucleotide pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33, limiting mitochondrial nucleotide import and accumulation of mtDNA. Deficiency of YME1L or the mitochondrial transcription factor A (TFAM) drives an mtDNA-dependent inflammatory response, which depends on SLC25A33 and is suppressed upon replenishment of cellular nucleotide pools. Metabolic insults that deplete cytosolic nucleotides trigger mtDNA-dependent immune responses. Our results thus identify mtDNA release and innate immune signaling as a metabolic response, offering new therapeutic opportunities in disease.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Hendrik Nolte

LAB HEAD: Thomas Langer

PROVIDER: PXD018097 | Pride | 2021-04-27

REPOSITORIES: Pride

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			Action	DRS
	0018.xlsx	Xlsx
	20190404_HN_0018_HaSp_ColID_456_DDA_sample_01.raw	Raw
	20190404_HN_0018_HaSp_ColID_456_DDA_sample_02.raw	Raw
	20190404_HN_0018_HaSp_ColID_456_DDA_sample_03.raw	Raw
	20190404_HN_0018_HaSp_ColID_456_DDA_sample_04.raw	Raw

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Project description:Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. We found that mtDNA-dependent immune signalling via the cGAS-STING pathway is under metabolic control and induced by cellular nucleotide deficiency. The mitochondrial protease YME1L preserves nucleotide pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33, limiting mitochondrial nucleotide transport and accumulation of mtDNA. Deficiency of YME1L or of the mitochondrial transcription factor A (TFAM) drives an mtDNA-dependent inflammatory response, which depends on SLC25A33 and is suppressed upon replenishment of cellular nucleotide pools. Depletion of cytosolic nucleotides upon starvation or downregulation of de novo nucleotide synthesis triggers mtDNA-dependent immune responses. Our results thus identify mtDNA release and innate immune signalling as a metabolic response, offering new therapeutic opportunities in disease.

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