Multiple RNA-binding proteins associated with long interspersed element-1 encoded ORF1p are targeted by the...

Systemic lupus erythematosus (SLE) is a relatively common autoimmune disease characterized by the presence of autoantibodies against nucleic acids and proteins that associate with them, such as the ORF1p protein encoded by the long interspersed element-1 (LINE-1 or L1). Because well-known lupus autoantigens like RO60 associate with ORF1p in macromolecular assemblies, together with many other RNA-binding proteins, we tested whether these other proteins are also recognized by IgG autoantibodies in SLE patients. By ELISAs and immunoblots, we detected autoantibodies in the serum of SLE patients recognizing proteins encoded by LARP7, MOV10, ZCCHC3, MEPCE, YARS2, RPL18A, RPL27A, and H2BC17 (p<0.05), but not CORO1B, DDX6, PABPC1, and PABPC4, and were mostly absent or low in healthy controls. The titers of antibodies against RO60, LARP7, MOV10, and MEPCE were higher (p<0.05) in those patients who also had anti-ORF1p autoantibodies. These antibodies also correlated with dsDNA antibodies, the presence of arthritis, and higher levels of type I interferons. A cluster analysis revealed that all these autoantibodies collectively identified patients with more active disease. We conclude that patients with SLE have elevated IgG autoantibodies not only against the L1-encoded ORF1p, but also against 8 other proteins that co-localize with ORF1p in RNA-rich granules. These autoantibodies are higher in patients who have autoantibodies to ORF1p and together correlate with elevated type I interferon levels. Our findings are compatible with the notion that ORF1p-containing ribonucleoprotein granules are a target of the autoimmunity in SLE.