Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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.
Immunity. 2019 Feb 19;50(2):334-347.e9. doi: 10.1016/j.immuni.2018.12.022. Epub 2019 Jan 29.
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.
内源性逆转录病毒 (ERV) 的转录水平升高和抗 ERV 抗体反应与狼疮发病机制有关。在狼疮易感小鼠中，非嗜性 ERV（NEERV）包膜糖蛋白 gp70 的过度产生和由此导致的肾炎发生，但 NEERV 的异常表达是否导致狼疮发病尚不清楚。本研究鉴定了抑制 NEERV（Snerv）1 和 2，即 KRAB 锌指蛋白（KRAB-ZFPs），通过结合 NEERV 长末端重复序列来募集转录调节剂 KAP1，从而抑制 NEERV。Snerv1/Snerv2 基因敲除小鼠的种系缺失增加了 NEERV 基因座的激活染色质修饰、转录和 gp70 表达。狼疮易感的新西兰黑色（NZB）和 129 小鼠与 Snerv1/Snerv2 基因敲除小鼠的 F1 杂交未能恢复 NEERV 的抑制，表明 SNERV 的缺失是导致狼疮自身抗原 gp70 过度产生的原因，该抗原促进易感小鼠肾炎的发生，并且 SNERV 编码 Sgp3（在 NZB 小鼠中）和 Gv-1 基因座（在 129 小鼠中）。狼疮患者中 ERV 的表达增加与三个假定的 ERV 抑制性 KRAB-ZFPs 呈负相关，这表明 KRAB-ZFP 介导的 ERV 控制的丧失可能导致人类狼疮发病机制。
