Posttranscriptional regulation of the inhibitor of apoptosis protein HIAP2 during cellular stress

Abstract

Apoptosis is a physiological process characteristic of pluricellular organisms leading to self-destruction of the cell. One of the hallmarks of apoptosis is the activation of caspases that in turn cleave cellular substrates, leading to an orderly disassembly of the cell. A family of intrinsic cellular inhibitor of Apoptosis (IAP) proteins mediates competitive inhibition of caspase activity. I have discovered that UVC stress in HEK293 cells leads to downregulation of HIAP2 expression that is due to mRNA destabilization. I have identified that there are four putative AU-rich (ARE) elements located within the 3'untranslated region of HIAP2 mRNA that are sufficient to mediate HIAP2 mRNA instability during UVC stress. I hypothesized that specific ARE-binding protein (AUBP) could interact with the HIAP2 AREs which results in the modulation of HIAP2 expression. To this end, I have identified hnRNPA1 as one of the HIAP2 3'UTR ARE binding proteins. HnRNP A1 is primarily nuclear but becomes localized into cytoplasm after exposure of cells to UVC. In addition, hnRNP A1 destabilizes HIAP2 mRNA under normal growth conditions and during UVC stress. Furthermore, more than one ARE may contribute to the binding of hnRNP A1 to the HIAP2 3'UTR. Lastly, knockdown of hnRNP A1 attenuates the UVC -- induced apoptosis suggesting that hnRNP A1 is an essential post-transcriptional modulator of HIAP2 expression.