The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression

Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren’s syndrome. However, whether Ro60 and its associated RNAs contribute to disease pathogenesis is unclear. We cataloged the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated pro-inflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60 positive SLE immune complexes contained Alu RNAs, and Alu transcripts were upregulated in SLE whole blood samples compared to controls. These findings establish a link between the lupus autoantigen Ro60, Alu retroelements and type I interferon.