The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV

Abstract

Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein, gp70, and resultant nephritis occur in lupus-prone mice. However, a NEERV repressor has not been identified to test if this association is causal. Here we identified suppressor of NEERV (Snerv) 1 & 2, Kruppel-associated box zinc finger proteins (KRAB-ZFP) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone NZB and 129 mice to Snerv1/2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice. Increased ERV expression in lupus patients was inversely correlated with expression of three putative ERV-suppressing KRAB-ZFP, suggesting that KRAB-ZFP-mediated ERV misexpression may contribute to human lupus pathogenesis.