Background The B cell activating factor (BAFF) is a potent survival factor involved in the pathogenesis of autoimmune diseases. Recently, the authors reported the discovery of a new transcript for BAFF, Δ4BAFF - lacking exon 4 - mainly detected in autoimmune diseases. Δ4BAFF acts as a transcription factor of its own gene. However, the mechanisms implicated in Δ4BAFF induction and up-regulation remain unknown. the analysed the mechanisms of induction and regulation of Δ4BAFF.
Materials and methods First, the authors tested if Δ4BAFF could be regulated by non-sense mediated decay (NMD) mechanisms, by blocking de novo protein synthesis. Secondly, the authors examined the effects of IFNγ on Δ4BAFF expression in different cell lines. Finally, to study the mechanisms implicated in the alternative splicing of exon 4, the authors transfected a minigene construct, centered on exon 4, into RAMOS cells.
Results Δ4BAFF is not subjected to NMD-dependent degradation, despite the theoretical prediction, indicating that the transcript is stable. Incubation of cell lines with IFNγ showed induction of Δ4BAFF transcript. The induction of Δ4BAFF increased the expression of membrane-bound and soluble forms of BAFF. The effects of IFNγ on Δ4BAFF induction were confirmed using a minigene functional analysis of splicing.
Conclusion Collectively, these results demonstrated that IFNγ induces Δ4BAFF, leading to an increase of BAFF. Our study provides an expanded conceptual view of BAFF gene regulation, and contributes to a better understanding of the mechanisms involved in BAFF up-regulation in autoimmunity. The authors expect to identify the proteins implicated in the control of BAFF exon 4 alternative mRNA splicing in these diseases.