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

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.