Systemic lupus erythematosus and increased risk to develop B cell malignancies: role of the p200-family proteins

Abstract

Systemic lupus erythematosus (SLE), an autoimmune disease, develops at a female-to-male ratio of 10:1. Increased serum levels of type I interferons (IFN-alpha/beta) and induction of "IFN-signature" genes are associated with an active SLE disease in patients. Moreover, SLE patients exhibit three- to four-fold increase in the risk of developing malignancies involving B cells, including non-Hodgkin lymphoma (NHL) and Hodgkin's lymphoma (HL). Interestingly, homozygous mice expressing a deletion mutant (the proline-rich domain deleted) of the p53 develop various types of spontaneous tumors, particularly of B cell origin upon aging. The deletion is associated with defects in transcriptional activation of genes by p53 and inhibition of DNA damage-induced apoptosis. Notably, increased levels of the p202 protein, which is encoded by the p53-repressible interferon-inducible Ifi202 gene, in B cells of female mice are associated with defects in B cell apoptosis, inhibition of the p53-mediated transcription of pro-apoptotic genes, and increased lupus susceptibility. In this review we discuss how increased levels of the p202 protein (and its human functional homologue IFI16 protein) in B cells increase lupus susceptibility and are likely to increase the risk of developing certain B cell malignancies. A complete understanding of the molecular mechanisms that regulate B cell homeostasis is necessary to identify SLE patients with an increased risk to develop B cell malignancies.

Fig. 1

Top panel: p53 protein and its structural domains: the transactivation domain (TAD), proline-rich domain (PRD), specific DNA-binding domain (DBD), tetramerization domain (4D), and C-terminal regulatory (CT) domain. The p202-binding region (amino acids residues 43-83) within the proline-rich domain of the p53 protein is indicated [46]. The amino acid residues (Δ63-85) that were deleted in the murine p53 protein in the study by Slatter et al. [34] are also indicated. The IFI16-binding region (amino acids residues 362-393) within the proline-rich domain of the human p53 protein is indicated [63]. Middle panel: p202 protein and its structural domains. The p53-binding region (amino acid residues 255-273) in the p202 protein is indicated. Lower panel: IFI16 protein and its structural domains. The p53-binding region (amino acid residues 155-476) in the IFI16 protein is indicated.

Fig. 2

Model for the proposed role of the p202 and IFI16 proteins in the regulation of B cell survival. (a) Increased levels of p202 in B cells from the B6.Nba2 congenic female mice are associated with defects in apoptosis [46]. The defect is associated with inhibition of the p53-mediated transcriptional activation of pro-apoptotic genes and inhibition of p53-mediated transcriptional repression of anti-apoptotic genes. The p202 protein binds to the PRD domain of the p53 [46]. The p202 protein also modulates the transcriptional activity of NF-κB in a cell type-dependent manner [57-59]. Increased levels of the p202 protein in splenic B cells from B6.Nba2 female mice are associated with the activation of NF-κB transcriptional activity. (b) Increased levels of IFI16 protein in immune cells are predicted to increase B cell survival by inhibiting the p53-mediated transcription of pro-apoptotic genes. The Pro/Pro genotype (as compared to the Arg/Arg genotype) of the p53 in SLE patients may increase the risk of developing B cell malignancies by up-regulating the expression of the IFI16 gene. The IFI16 protein activates the NF-κB transcriptional activity in endothelial cells [68].