A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen

Abstract

Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24 -60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs. Because the Ro protein also binds misfolded 5S rRNA precursors, it is proposed to function in a quality-control pathway for ribosome biogenesis. Consistent with a role in the recognition or repair of intracellular damage, an orthologue of Ro in the radiation-resistant eubacterium Deinococcus radiodurans contributes to survival of this bacterium after UV irradiation. Here, we show that mice lacking the Ro protein develop an autoimmune syndrome characterized by anti-ribosome antibodies, anti-chromatin antibodies, and glomerulonephritis. Moreover, in one strain background, Ro ؊/؊ mice display increased sensitivity to irradiation with UV light. Thus, one function of this major human autoantigen may be to protect against autoantibody development, possibly by sequestering defective ribonucleoproteins from immune surveillance. Furthermore, the finding that mice lacking the Ro protein are photosensitive suggests that loss of Ro function could contribute to the photosensitivity associated with anti-Ro antibodies in humans.

A conserved motif of vertebrate Y RNAs essential for chromosomal DNA replication

“…Our demonstration that the truncated mutant USL RNA can functionally substitute for wt Y RNA in vitro, and in vivo also provides an explanation for the observation by Northern blotting that full-length mouse Y RNA levels are reduced in Ro60 knockout cells without an apparent inhibition of DNA replication Xue et al 2003). Provided that Ro60 depletion leads to increased nucleolytic degradation of Y RNAs Xue et al 2003), any resulting fragments containing only the 9-bp upper stem RNA duplex would still be functionally active and available to support chromosomal DNA replication, as seen in our RNAi rescue experiments.…”

“…In vertebrates, the binding site for Ro60 is adjacent to the domain essential for DNA replication, and thus insulates it from the 59 and 39 ends of the RNA. In light of our data, it is therefore tempting to speculate that although Ro60 is dispensable for DNA replication Xue et al 2003;Christov et al 2006), it may nonetheless be involved in DNA replication indirectly, either by protecting or insulating the replication domain from exonucleases, or by regulating the intracellular localization of Y RNAs.…”

Noncoding human Y RNAs are overexpressed in tumours and required for cell proliferation

“…Deletion of the Y RNA-interacting protein Ro60 leads to reduced levels of homologous mouse Y1 and Y3 RNA expression levels in adult brain tissue and embryonic stem (ES) cells Xue et al, 2003). Ro60 knockout mice are viable and no proliferation defects were reported for the mutant ES cells.…”

Genetic Dissection of Spontaneous Autoimmunity Driven by 129-Derived Chromosome 1 Loci When Expressed on C57BL/6 Mice

“…This region on chromosome 1 is rich in genes with immunologic functions including Apcs (13), Fcgr2b (14), Cr2 (15), Daf1 (16), Pdcd-1 (17), and Ro (18). All these genes have been inactivated by gene-targeting and the knockout models displayed a variable degree of autoimmunity.…”