YME1L1 KnockOut MEF Cells Whole Proteomics

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.

胞质线粒体DNA（mtDNA）可引发I型干扰素应答，但诱导线粒体释放mtDNA的信号机制仍未阐明。我们发现，经由cGAS-STING通路的mtDNA依赖性免疫信号通路受代谢调控，并可由细胞核苷酸匮乏诱导。线粒体蛋白酶YME1L通过促进核苷酸从头合成，以及降解嘧啶核苷酸转运体SLC25A33，从而限制线粒体核苷酸摄取与mtDNA积累，维持细胞核苷酸池稳态。YME1L或线粒体转录因子A（TFAM）的缺陷会触发mtDNA依赖性炎症应答，该应答依赖于SLC25A33，且可通过补充细胞核苷酸池得到抑制。耗尽胞质核苷酸的代谢应激可触发mtDNA依赖性免疫应答。综上，本研究结果将mtDNA释放与天然免疫信号通路鉴定为一类代谢响应，为疾病治疗提供了全新的治疗思路与靶点。