Mitochondrial Lon protease promotes CD4 T cell activation by activating the cGAS-STING-TBK1 axis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive CD4 T cells play an essential role. We extracted CD4 T cells from SLE-prone Fcgr2b mice to elaborate the mechanism of mitochondrial Lon protease in CD4 T cell activation in SLE. Transcriptome sequencing was performed in SLE-prone Fcgr2b mice, and the stimulator of interferon gene (STING) related to SLE was obtained. It was demonstrated that STING expression was elevated in CD4 T cells in SLE-prone Fcgr2b mice. The downstream genes and pathways of STING were predicted by GO and KEGG approaches. The data indicated that STING regulated IFN signaling to promote CD4 T cell activation in SLE-prone Fcgr2b mice. Next, the interaction of cGAS, STING, TBK1, and IFN-I was verified by Co-IP assay. Moreover, the roles of cGAS, STING, and TBK1 in activating CD4 T cells from SLE-prone Fcgr2b mice were evaluated using gain- or loss-of-function experiments. Mechanistically, cGAS upregulated the IFN-I signaling pathway by directly interacting with STING and TBK1, contributing to CD4 T cell activation. Besides, cytosolic mtDNA could activate CD4 T cell activation in SLE-prone Fcgr2b mice by upregulating the cGAS-STING-TBK1 axis. The function of mitochondrial Lon protease in oxidative damage and mtDNA release in CD4 T cells of SLE-prone Fcgr2b mice were explored. Mitochondrial Lon protease enhanced mtDNA release into the cytoplasm under oxidative stress. Collectively, our work indicates that mitochondrial Lon protease enhances CD4 T cell activation by inducing mtDNA leakage and offers new candidate targets for developing diagnostic and therapeutic strategies.