1. Mitochondrial DNA Programs Lactylation of cGAS to Induce IFN Responses in Patients with Systemic Lupus Erythematosus.
- Author
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Zhang J, Ji H, Liu M, Zheng M, Wen Z, and Shen H
- Subjects
- Humans, Interferon Type I metabolism, Interferon Type I immunology, Female, Glycolysis, Animals, Mice, Signal Transduction immunology, Mitochondria metabolism, Mitochondria immunology, Male, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Lactic Acid metabolism, Monocytes immunology, Monocytes metabolism, THP-1 Cells, Membrane Proteins metabolism, Membrane Proteins genetics, Adult, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic genetics, Nucleotidyltransferases metabolism, Nucleotidyltransferases genetics, DNA, Mitochondrial immunology, DNA, Mitochondrial genetics
- Abstract
Mitochondrial DNA (mtDNA) is frequently released from mitochondria, activating cGAS-STING signaling and inducing type I IFNs (IFN-Is) in systemic lupus erythematosus (SLE). Meanwhile, whether and how the glycolytic pathway was involved in such IFN-I responses in human SLE remain unclear. In this study, we found that monocytes from SLE patients exerted robust IFN-I generation and elevated level of cytosolic mtDNA. Transfection of mtDNA into THP-1 macrophages was efficient in inducing IFN-I responses, together with the strong glycolytic pathway that promoted lactate production, mimicking the SLE phenotype. Blockade of lactate generation abrogated such IFN-I responses and, vice versa, exogenous lactate enhanced the IFN-I generation. Mechanistically, lactate promoted the lactylation of cGAS, which inhibited its binding to E3 ubiquitination ligase MARCHF5, blocking cGAS degradation and leading to strong IFN-I responses. In accordance, targeting lactate generation alleviated disease development in humanized SLE chimeras. Collectively, cytosolic mtDNA drives metabolic adaption toward the glycolytic pathway, promoting lactylation of cGAS for licensing IFN-I responses in human SLE and thereby assigning the glycolytic pathway as a promising therapeutic target for SLE., (Copyright © 2024 by The American Association of Immunologists, Inc.)
- Published
- 2024
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