Sprenger, Hans-Georg ORCID: 0000-0002-9864-5995, MacVicar, Thomas ORCID: 0000-0001-9846-6359, Bahat, Amir, Fiedler, Kai Uwe, Hermans, Steffen, Ehrentraut, Denise, Ried, Katharina ORCID: 0000-0003-4058-9588, Milenkovic, Dusanka, Bonekamp, Nina ORCID: 0000-0001-9748-8089, Larsson, Nils-Goeran, Nolte, Hendrik, Giavalisco, Patrick and Langer, Thomas (2021). Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity. Nat. Metab., 3 (5). S. 636 - 666. BERLIN: NATURE RESEARCH. ISSN 2522-5812

Full text not available from this repository.

Abstract

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 synthase-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 inflammation 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. Sprenger et al. find that cytosolic pyrimidine levels regulate the release of mitochondrial DNA and activation of cGAS-STING.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sprenger, Hans-GeorgUNSPECIFIEDorcid.org/0000-0002-9864-5995UNSPECIFIED
MacVicar, ThomasUNSPECIFIEDorcid.org/0000-0001-9846-6359UNSPECIFIED
Bahat, AmirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiedler, Kai UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hermans, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehrentraut, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ried, KatharinaUNSPECIFIEDorcid.org/0000-0003-4058-9588UNSPECIFIED
Milenkovic, DusankaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonekamp, NinaUNSPECIFIEDorcid.org/0000-0001-9748-8089UNSPECIFIED
Larsson, Nils-GoeranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giavalisco, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-579381
DOI: 10.1038/s42255-021-00385-9
Journal or Publication Title: Nat. Metab.
Volume: 3
Number: 5
Page Range: S. 636 - 666
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2522-5812
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/57938

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item