Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions

Abstract

Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.

Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress

“…Tomar et al () induced ER stress by tunicamycin in HEK293 and MCF7 cells, and found that the TRIM13 regulates caspase‐8 ubiquitination and translocation to autophagosomal membranes. Deegan et al () also induced ER stress by tunicamycin and thapsigargin in cells lacking caspase‐9 or Bax and Bak, found the protein complex composed of Atg5, FADD, and pro‐caspase‐8, and identified apoptotic cell death depending on caspase‐8 as the apical caspase. Furthermore, they inhibited autophagy by knockdown of Atg5 and Atg7, and showed that caspase‐8‐dependent cell death were alleviated.…”

Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death

“…Autophagy is a highly conserved process that is implicated in maintaining the cellular metabolic balance and n 4 is often activated under stressful conditions. This process is generally cytoprotective [19]; however, excessive activation of autophagy will result in the excessive self-digestion and autophagic cell death [20]. We sought to clarify the role of autophagy in regulating cell death after NPRA silencing to gain important implications for cell death control and cancer therapies.…”

Cell death induced by endoplasmic reticulum stress

“…TRIM13 was also shown to be necessary for the translocation of caspase-8 to autophagosomal membranes upon ER stress stimuli, where it interacts with p62 and the lipidated form of LC3. Moreover, it was recently shown that ER stressors such as tunicamycin and thapsigargin induce, in cells lacking caspase-9 or Bax and Bak, apoptotic cell death depending on caspase-8 as the apical caspase [64]. Knockdown of autophagic genes such as Atg5 and Atg7 protected from caspase-8 dependent cell death.…”