Alternative splicing of Bnip3 modulates calcium signals to prevent mitochondrial-dependent cell death and regulate gene expression.
The Bnip3 cell death gene is prominently expressed in many hypoxic-ischemic related pathologies, such as heart failure and necrotising enterocolitis in the intestine. Two isoforms of Bnip3 have been described in the literature: a pro-death full-length protein (Bnip3FL) and a pro-survival protein lacking exon3 (Bnip3∆Ex3). Bnip3∆Ex3 acts as an endogenous inhibitor of Bnip3FL function, yet how Bnip3∆Ex3 serves this function is unknown. In gain-of-function experiments, I use combinations of cell lines and primary cells to dissect the mechanism(s) of Bnip3∆Ex3 action. Herein, I report that Bnip3∆Ex3 expression orchestrates an intricate calcium signalling cascade that has two cellular outcomes. First, calcium signals avert mitochondrially-dependent cell death. Second, these calcium signals modulate transcriptional regulators and gene expression causing morphological cell changes. These data provide original evidence that Bnip3∆Ex3 has the potential to mitigate the detrimental effects of hypoxia and Bnip3FL signalling by activating a complex signalling cascade and multiple survival pathways.
Cell biology, Cell death, Bnip3 splicing, Calcium signalling