Department of Pathology and Immunology, University of Geneva, 1211 Geneve 4, Switzerland.
J Autoimmun. 2011 Dec;37(4):311-8. doi: 10.1016/j.jaut.2011.09.001. Epub 2011 Oct 7.
The envelope glycoprotein gp70 of endogenous retroviruses implicated in murine lupus nephritis is secreted by hepatocytes and its expression is controlled by Sgp3 (serum gp70 production 3) and Sgp4 loci derived from lupus-prone mice. Among three different endogenous retroviruses (ecotropic, xenotropic and polytropic), xenotropic viruses are considered to be the major source of serum gp70. Although the abundance of xenotropic viral gp70 RNA in livers was up-regulated by the presence of these two Sgp loci, it has not yet been clear whether Sgp3 and Sgp4 regulate the expression of a fraction or multiple xenotropic viruses present in mouse genome. To address this question, we determined the genetic origin of xenotropic viral sequences expressed in wild-type and two different Sgp congenic C57BL/6 mice. Among 14 xenotropic proviruses present in the C57BL/6 genome, only two proviruses (Xmv10 and Xmv14) were actively transcribed in wild-type C57BL/6 mice. In contrast, Sgp3 enhanced the transcription of Xmv10 and induced the transcription of three additional xenotropic viruses (Xmv15, Xmv17 and Xmv18), while Sgp4 induced the expression of a different xenotropic virus (Xmv13). Notably, stimulation of TLR7 in Sgp3 congenic C57BL/6 mice led to a highly enhanced expression of potentially replication-competent Xmv18. These results indicated that Sgp3 and Sgp4 independently regulated the transcription of distinct and restricted sets of xenotropic viruses in trans, thereby promoting the production of nephritogenic gp70 autoantigens. Furthermore, the induced expression of potentially replication-competent xenotropic viruses by Sgp3 may contribute to the development of autoimmune responses against gp70 through the activation of TLR7.
内源性逆转录病毒的 envelope 糖蛋白 gp70 与小鼠狼疮肾炎有关，它由肝细胞分泌，其表达受 Sgp3（血清 gp70 产生 3）和 Sgp4 基因座控制，这些基因座来源于狼疮易感小鼠。在三种不同的内源性逆转录病毒（ecotropic、xenotropic 和 polytropic）中，xenotropic 病毒被认为是血清 gp70 的主要来源。尽管这两个 Sgp 基因座的存在使肝脏中 xenotropic 病毒 gp70 RNA 的丰度上调，但尚不清楚 Sgp3 和 Sgp4 是否调节存在于小鼠基因组中的一部分或多种 xenotropic 病毒的表达。为了解决这个问题，我们确定了在野生型和两种不同 Sgp 同基因 C57BL/6 小鼠中表达的 xenotropic 病毒序列的遗传起源。在 C57BL/6 基因组中存在的 14 个 xenotropic 前病毒中，只有两个前病毒（Xmv10 和 Xmv14）在野生型 C57BL/6 小鼠中被转录。相比之下，Sgp3 增强了 Xmv10 的转录，并诱导了另外三个 xenotropic 病毒（Xmv15、Xmv17 和 Xmv18）的转录，而 Sgp4 诱导了另一个 xenotropic 病毒（Xmv13）的表达。值得注意的是，在 Sgp3 同基因 C57BL/6 小鼠中刺激 TLR7 会导致潜在复制能力的 Xmv18 的高度增强表达。这些结果表明，Sgp3 和 Sgp4 独立地在转位过程中调节不同和受限的 xenotropic 病毒转录组，从而促进了致肾炎 gp70 自身抗原的产生。此外，Sgp3 诱导的潜在复制能力的 xenotropic 病毒的表达可能通过激活 TLR7 导致针对 gp70 的自身免疫反应的发展。
