Disruption of Mutually Negative Regulatory Feedback Loop between Interferon-Inducible p202 Protein and the E2F Family of Transcription Factors in Lupus-Prone Mice

Abstract

Studies have identified IFN-inducible Ifi202 gene as a lupus susceptibility gene (encoding p202 protein) in mouse models of lupus disease. However, signaling pathways that regulate the Ifi202 expression in cells remain to be elucidated. We found that steady-state levels of Ifi202 mRNA and protein were high in mouse embryonic fibroblasts (MEFs) from E2F1 knockout (E2F1−/−) and E2F1 and E2F2 double knockout (E2F1−/−E2F2−/−) mice than isogenic wild-type MEFs. Moreover, overexpression of E2F1 in mouse fibroblasts decreased expression of p202. Furthermore, expression of E2F1, but not E2F4, transcription factor in mouse fibroblasts repressed the activity of 202-luc-reporter in promoter-reporter assays. Interestingly, the E2F1-mediated transcriptional repression of the 202-luc-reporter was independent of p53 and pRb expression. However, the repression was dependent on the ability of E2F1 to bind DNA. We have identified a potential E2F DNA-binding site in the 5′-regulatory region of the Ifi202 gene, and mutations in this E2F DNA-binding site reduced the E2F1-mediated transcriptional repression of 202-luc-reporter. Because p202 inhibits the E2F1-mediated transcriptional activation of genes, we compared the expression of E2F1 and its target genes in splenic cells from lupus-prone B6.Nba2 congenic mice, which express increased levels of p202, with age-matched C57BL/6 mice. We found that increased expression of Ifi202 in the congenic mice was associated with inhibition of E2F1-mediated transcription and decreased expression of E2F1 and its target genes that encode proapoptotic proteins. Our observations support the idea that increased Ifi202 expression in certain strains of mice contributes to lupus susceptibility in part by inhibiting E2F1-mediated functions.

Absent in Melanoma 2 proteins in SLE

“…Mouse embryonic fibroblasts from E2F1-knockout (E2F1 −/− ) and E2F1 and E2F2 double knockout (E2F1 −/− E2F2 −/− ) mice expressed higher constitutive levels of Ifi202 mRNA and protein than isogenic wild type MEFs [97]. Further, overexpression of the E2F1 transcription factor in mouse fibroblasts transcriptionally repressed the expression of the Ifi202 gene and decreased the levels of p202 protein.…”

“…Of note, an increased expression of the p202 protein in splenic cells from the B6. Nba2 congenic mice as compared with age-matched C57BL/6 mice associated with inhibition of the E2F1-mediated transcription of genes that encoded for pro-apoptotic proteins [97]. Because activation of the E2F1 transcription factor promotes cell death of auto-reactive T cells [98] and both E2F1 and E2F2 transcription factors are implicated in the regulation of autoimmunity [99], our observations suggested that increased levels of the p202 protein in immune cells increase cell survival in part by inhibiting the E2F1-mediated pro-apoptotic activity.…”

Absent in melanoma 2 proteins in the development of cancer

“…Accordingly, the constitutive levels of p202 mRNA and protein are higher in cells from female mice than the agematched males [55]. However, the p202 expression is suppressed by activated p53 [56], growth factors [57], and E2F1 [58]. p202 lacks the PYD in the N-terminus [2].…”

The inflammasome and lupus

“…Others, however, have demonstrated that inhibition of AIM2 may promote lupus pathogenesis. In mice, another interferon-inducible p200 family member, p202, is upregulated in many lupus-prone strains(43, 44). p202 negatively regulates AIM2 inflammasome activation, consequently decreasing cell death and promoting prolonged type I IFN production in response to cytosolic DNA(45*).…”