Effect of Subcellular Translocation of Protein Disulfide Isomerase on Tetrachlorobenzoquinone-Induced Signaling Shift from Endoplasmic Reticulum Stress to Apoptosis

Abstract

Our previous studies illustrated tetrachlorobenzoquinone (TCBQ)-caused toxicities in neuron-like cells which imply its association with neurodegenerative disorders. Although it is known that TCBQ induces oxidative damage that in turn results in endoplasmic reticulum (ER) stress and apoptosis, it is unclear how TCBQ triggers the signaling switch from pro-survival (to restore cellular homeostasis) to pro-death (trigger apoptosis). Protein disulfide isomerase family proteins (PDIs) regulate the progress of various neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. We tested the hypothesis that subcellular translocation of PDIs implicates the survival/death signaling switch by inducing mitochondrial outer membrane permeabilization (MOMP). The rat pheochromocytoma PC12 cells were exposed to TCBQ, and the concentration-dependent ER stress was observed upon TCBQ treatment, as indicated by the increase in inositol-requiring kinase/endonuclease 1α (IRE1α) phosphorylation, C/EBP homologous protein (CHOP) expression, X-box-binding protein 1 (XBP1) splicing, and caspase 12 activation. Interestingly, pharmacological (or siRNA) abrogation of PDIA1/PDIA3 aggravated the loss of cell viability induced by the relatively low concentration (10 μM) of TCBQ. However, inhibition of PDIA1/PDIA3 rescued the high concentration (20 μM) of TCBQ-induced cell death. Further mechanistic study illustrated that PDIs initially acted to restore cellular homeostasis to pro-survival but that the constant ER stress promoted the signaling switch to pro-apoptotis by the release of PDIA1/PDIA3 from the ER lumen to induce Bak-dependent MOMP. Our findings suggested that subcellular translocation of PDIs determined the "life or death" fate of PC12 cells to TCBQ-induced oxidative insult.

Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress

“…While the larger scope of ER reflux remains to be defined, the process could conceivably extend to many endogenous ERresident proteins (and maturing secretory cargo). Indeed, our finding that PDI1 and CPR5 proteins are recovered (through an HLJ1-dependent mechanism) in the cytosol during ER stress is consistent with the possibility that these proteins are also reflux substrates (and provides an explanation for previous enigmatic reports of how ER chaperones could be found in the cytosol) (39)(40)(41). Physiologically, it is conceivable that ER protein reflux, by clearing the ER of luminal proteins during ER stress, may have an adaptive benefit and may work in parallel with other ER protein quality control mechanisms such as ERAD and protein translocational attenuation, referred to as preemptive quality control (11).…”

Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress

“…While the larger scope of ER reflux remains to be defined, the process could conceivably extend to many endogenous ER-resident proteins (and maturing secretory cargo). Indeed, our finding that PDI1 and CPR5 proteins are recovered (through an HLJ1-dependent mechanism) in the cytosol during ER stress is consistent with the possibility that these proteins are also reflux substrates (and provides an explanation for previous enigmatic reports of how ER chaperones could be found in the cytosol) [39][40][41]. Physiologically, it is conceivable that ER protein reflux, by clearing the ER of luminal proteins during ER stress, may have an adaptive benefit and may work in parallel with other ER protein quality control mechanisms such as ERAD and protein translocational attenuation referred to as pre-emptive quality control (pre-QC) [11].…”

Zinc oxide nanoparticles effectively regulate autophagic cell death by activating autophagosome formation and interfering with their maturation

“…PC12 cell line, one of the widely used in vitro experimental models, has neuronal characteristics, such as expressing dopaminergic markers, and is capable of undergoing a variety of regulated cell death, such as apoptosis [23], necrosis [24], autophagy [25] and ferroptosis [26]. Thus, PC12 cells are often used to study the pathogenesis of many neurological diseases depending on the external chemicals [26,27].…”