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Immunity. 2019 Feb 19;50(2):334-347.e9. doi: 10.1016/j.immuni.2018.12.022. Epub 2019 Jan 29.

The Lupus Susceptibility Locus Sgp3 Encodes the Suppressor of Endogenous Retrovirus Expression SNERV.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: akiko.iwasaki@yale.edu.

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.

KEYWORDS:

Endogenous retrovirus; Gv1; KRAB-ZFP; Sgp3; autoimmunity; gp70; lupus nephritis; systemic lupus erythematosus; transcriptional repression

PMID:
30709743
PMCID:
PMC6382577
[Available on 2020-02-19]
DOI:
10.1016/j.immuni.2018.12.022
[Indexed for MEDLINE]

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