Increased Expression of Ifi202, an IFN-Activatable Gene, in B6.Nba2 Lupus Susceptible Mice Inhibits p53-Mediated Apoptosis

Abstract

Increased expression of p202 protein (encoded by the Ifi202 gene) in splenocytes derived from B6.Nba2 mice (congenic for the Nba2 interval derived from the New Zealand Black mice) was correlated with defects in apoptosis of splenic B cells and increased susceptibility to develop systemic lupus erythematosus. We have now investigated the molecular mechanisms by which increased expression of p202 in B6.Nba2 cells contributes to defects in apoptosis. In this study, we report that increased expression of p202 in the B6.Nba2 splenocytes, as compared with cells derived from the parental C57BL/6 (B6) mice, was correlated with increased levels of p53 protein and inhibition of p53-mediated transcription of target genes that encode proapoptotic proteins. Conversely, knockdown of p202 expression in B6.Nba2 cells resulted in stimulation of p53-mediated transcription. We found that p202 bound to p53 in the N-terminal region (aa 44–83) comprising the proline-rich region that is important for p53-mediated apoptosis. Consistent with the binding of p202 to p53, increased expression of p202 in B6.Nba2 mouse embryonic fibroblasts inhibited UV-induced apoptosis. Taken together, our observations support the idea that increased expression of p202 in B6.Nba2 mice increases the susceptibility to develop lupus, in part, by inhibiting p53-mediated apoptosis.

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

“…Consistent with inhibition of the transcriptional activity of the above factors by p202, the increased expression of p202 in cell lines, depending on the cell context, either sensitizes cells to apoptosis or decrease the susceptibility to apoptosis (21). Importantly, we found that increased expression of p202 in splenic B6.Nba2 cells was associated with inhibition of p53-mediated transcription of proapoptotic genes and defects in apoptosis of cells (51). Therefore, our earlier observations that certain E2Fs, such as E2F1 and E2F2, repress the transcription of the Ifi202 gene are consistent with our above observations.…”

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

“…Also, as expected, Ifi202 failed to get upregulated in IFNAR-deficient splenocytes after exposure to IFNabs in vitro. As Ifi202 is known to bind cell apoptosis and cycle control proteins such as p53BP and retinoblastoma protein, [36][37][38] the reduced levels of Ifi202 in total splenocytes from IFNAR-deficient B6.Nba2 mice may be directly related to the lack of splenomegaly in these mice.…”

Overexpression of interferon-activated gene 202 (Ifi202) correlates with the progression of autoimmune glomerulonephritis associated with the MRL chromosome 1

“…IFI16, the human homolog of mouse Ifi202, was found to be mainly expressed in endothelial cells, whereas Ifi202 was found to be expressed in various cells such as bone marrow cells, fibroblasts, lymphocytes, and myoblasts in vitro. 4,[17][18][19][20] On the basis of these findings, it was proposed that the overexpression of Ifi202 may occur in not only glomerular and tubular cells but also interstitial cells including lymphocytes in the kidneys of B6.MRLc1(82-100) mice. Ifi202 protein is generally induced by IFNs and has been suggested to contribute to the regulation of cellular differentiation, proliferation, and survival by controlling the activities of several transcription factors.…”