The role of microRNAs during endoplasmic reticulum stress induced cell death
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Endoplasmic Reticulum (ER) stress occurs in response to negative insult or stimuli to the cell. It induces a pathway called the unfolded protein response (UPR) which can alleviate stress and restore the cell to its ¿healthy state¿ or if the stress cannot be overcome, the UPR induces pro-apoptotic signalling events to eliminate the stressed cell. Such pathways have been associated with many pathological conditions. In cancer for instance, pro-survival UPR signalling can be utilized to compromise apoptosis induction and enhance cell growth and survival. In other diseases like neurodegeneration and diabetes excessive apoptosis and ER stress is observed and enhances disease progression. The mechanisms controlling the switch between pro-survival and pro-apoptotic ER stress responses is not fully elucidated. We considered that the small non-coding RNAs called microRNAs (miRNAs) may have a role in ER stress induced cell death and may fine tune the signalling events that determine cell fate or that ER stress may regulate miRNA expression to modulate stress responses. Two approaches for investigating the role of miRNA during ER stress induced cell death were employed. Firstly, a global approach was taken in which the biogenesis pathway of miRNAs was compromised to understand if miRNAs were important for ER stress induced apoptosis. This study revealed that cells with compromised miRNA biogenesis machinery were resistant to ER stress induced cell death but not other inducers of apoptosis. Although loss of global miRNA expression had no effect on the UPR, induction of the intrinsic apoptosis pathway was delayed, upstream of the mitochondria. This was due to altered levels of the BCL-2 family members which subsequently prevented BAX activation and permeabilisation of the outer mitochondrion membrane. Secondly, a candidate approach was used to determine if miRNA themselves are regulated during ER stress induced cell death. miRNA microarray analysis was used to screen for miRNA differentially regulated upon ER stress. This revealed that miRNA of the miR-17-92 cluster and their paralog cluster miR-106b-25 were downregulated during ER stress induced cell death in a PERK dependant manner. Further analysis revealed that the PERK regulated transcription factors NRF2 and ATF4 were responsible for this repression. The BH3 only protein, BIM a known target of these miRNA, increased in their absence and lead to apoptosis. This work illustrates an essential role for miRNA in ER stress -induced cell death.