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

Rebecca S. Treger, Scott D. Pope, Yong Kong, Maria Tokuyama, Manabu Taura, View ORCID ProfileAkiko Iwasaki
doi: https://doi.org/10.1101/487231
Rebecca S. Treger
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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Scott D. Pope
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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Yong Kong
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2Department of Molecular Biophysics and Biochemistry, W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT 06520, USA.
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Maria Tokuyama
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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Manabu Taura
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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Akiko Iwasaki
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
3Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
4Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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  • ORCID record for Akiko Iwasaki
  • For correspondence: akiko.iwasaki@yale.edu
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Summary

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, Krüppel-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.

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Posted December 04, 2018.
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The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV
Rebecca S. Treger, Scott D. Pope, Yong Kong, Maria Tokuyama, Manabu Taura, Akiko Iwasaki
bioRxiv 487231; doi: https://doi.org/10.1101/487231
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The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV
Rebecca S. Treger, Scott D. Pope, Yong Kong, Maria Tokuyama, Manabu Taura, Akiko Iwasaki
bioRxiv 487231; doi: https://doi.org/10.1101/487231

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