부산대학교 도서관

Keywords autoimmunity; systemic lupus erythematosus; CANDLE syndrome; human erythropoiesis; mitochondrial DNA; proteasome; HIF2a; mitophagy; interferon; cGAS Highlights * HIF2[alpha] degradation promotes UPS activation and mitophagy during human erythropoiesis * Defective HIF2[alpha] degradation leads to accumulation of Mito.sup.+ RBCs in SLE patients * Uptake of opsonized Mito.sup.+ RBCs by macrophages induces IFN production via cGAS/STING * Highest ISG scores define SLE patients with Mito.sup.+ RBCs and opsonizing antibodies Summary Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito.sup.+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito.sup.+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito.sup.+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.