Endoplasmic Reticulum Stress Induces miR-706, A Pro-Cell Death
microRNA, in A Protein Kinase RNA-Like ER Kinase
(PERK) and Activating Transcription Factor 4
(ATF4) Dependent Manner
The first two authors equally contributed to this work.
Wang X, Han Y, Hu G, Guo J, Chen H. Endoplasmic reticulum stress induces miR-706, a pro-cell death microRNA, in a protein kinase RNA-like ER kinase (PERK) and activating transcription factor 4 (ATF4) dependent manner. Cell J. 2020; 22(3): 394-400. doi: 10.22074/cellj.2020.6873.
Endoplasmic reticulum (ER) stress causes an adaptive response initiated by protein kinase RNA-like ER kinase (PERK), Ire1 and ATF6. It has been reported that these upstream regulators induce microRNAs. The current study was designed to find a novel microRNA that mediates ER stress components and finally contributes to cell fate decision.
Materials and Methods
In this experimental study, miR-706 levels were checked under different conditions of ER stress induced by Thapsigargin, Tunicamycin or low glucose media. PERK and ATF4 were knocked-down by administration of lentivirus-mediated short hairpin RNA to explore the effect of ER stress related proteins on miR-706 expression. The effect of miR-706 on caspase activity and apoptosis inhibitor 1 (CAAP1) levels were examined by using mimic-miR-706. The role of CAAP1 in inhibiting cell death (measured by Annexin V staining) and contributing to patient overall survival (measured by Kaplan-Meier estimate) were further confirmed by anti- miR-706 and CAAP1 knock-down.
We showed that Thapsigargin or Tunicamycin triggered ER stress leading to the induction of miR-706. miR-706 induction is dependent on PERK and its downstream regulator ATF4, as knocking-down of PERK and ATF4 suppressed miR-706 induction in response to ER stress. Knocking-down of miR-706 reduces cell death triggered by ER stress, indicating that miR-706 is pro-cell death microRNA. We further identified CAAP1 as a miR-706 target in regulating ER stress initiated cell death.
Collectively, our results pointed to an ER signaling network consisting of proteins, microRNA and novel target.