A novel transmembrane protein defines the endoplasmic reticulum stress-induced cell death pathway

Mitochondrial membrane potential (ΔΨ_m) maintenance is physiologically critical in cells; its loss causes apoptotic signalling and cell death. Accumulating DNA mutations and unfolded proteins in stressed cells activate signalling pathways for cell death induction. Cancer cells often fail to die even in the presence of some death signalling proteins. Here, we report a short hairpin RNA (shRNA) with an artificial sequence, denoted Psi1 shRNA, which leads to ΔΨ_m loss in HCT116 cells. The Psi1 shRNA target gene was shown to encode transmembrane protein 117 (TMEM117). TMEM117 knockdown led to ΔΨ_m loss, increased Reactive Oxygen Species levels, up-regulation of an endoplasmic reticulum (ER) stress sensor C/EBP homologous protein and active Caspase-3 expression, and cell growth impairment, altering homeostasis towards cell death. TMEM117 levels were down-regulated in response to the ER stressor thapsigargin and decreased when cells showed ΔΨ_m loss. These results suggested that TMEM117 RNAi allowed apoptotic cell death. Therefore, TMEM117 probably mediates the signalling of ΔΨ_m loss in ER stress-mediated mitochondria-mediated cell death.

Cell death; Endoplasmic reticulum stress; Mitochondrial membrane potential; RNAi.