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, but whether NEERV mis-expression contributes to lupus etiology is unclear. Here we identified suppressor of NEERV (Snerv) 1 and 2, Krüppel-associated box zinc-finger proteins (KRAB-ZFPs) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/Snerv2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone New Zealand Black (NZB) and 129 mice to Snerv1/Snerv2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice and that SNERV encodes for Sgp3 (in NZB mice) and Gv-1 loci (in 129 mice). Increased ERV expression in lupus patients inversely correlated with three putative ERV-suppressing KRAB-ZFPs, suggesting that loss of KRAB-ZFP-mediated ERV control may contribute to human lupus pathogenesis.
Subject(s)
Carrier Proteins/immunology , Endogenous Retroviruses/immunology , Glycoproteins/immunology , Lupus Nephritis/immunology , Molecular Chaperones/immunology , Nuclear Proteins/immunology , Repressor Proteins/immunology , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Endogenous Retroviruses/genetics , Endogenous Retroviruses/metabolism , Gene Expression Regulation/immunology , Genetic Predisposition to Disease/genetics , Glycoproteins/genetics , Glycoproteins/metabolism , HEK293 Cells , Humans , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Lupus Nephritis/genetics , Lupus Nephritis/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Inbred NZB , Mice, Knockout , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolismABSTRACT
The genomes of inbred mice harbor around 50 endogenous murine leukemia virus (MLV) loci, although the specific complement varies greatly between strains. The Gv1 locus is known to control the transcription of endogenous MLVs and to be the dominant determinant of cell-surface presentation of MLV envelope, the GIX antigen. Here, we identify a single Krüppel-associated box zinc finger protein (ZFP) gene, Zfp998, as Gv1 and show it to be necessary and sufficient to determine the GIX+ phenotype. By long-read sequencing of bacterial artificial chromosome clones from 129 mice, the prototypic GIX+ strain, we reveal the source of sufficiency and deficiency as splice-acceptor variations and highlight the varying origins of the chromosomal region encompassing Gv1. Zfp998 becomes the second identified ZFP gene responsible for epigenetic suppression of endogenous MLVs in mice and further highlights the prominent role of this gene family in control of endogenous retroviruses.