The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

Abstract

Autophagy is protective in cadmium (Cd)-induced oxidative damage. Endoplasmic reticulum (ER) stress has been shown to induce autophagy in a process requiring the unfolded protein response signalling pathways. Cd treatment significantly increased senescence in neuronal cells, which was aggravated by 3-MA or silencing of Atg5 and abolished by rapamycin. Cd increased expression of ER stress regulators Bip, chop, eIf2α, and ATF4, and activated autophagy as evidenced by upregulated LC3. Moreover, the ER stress inhibitor mithramycin inhibited the expression of ER stress protein chaperone Bip and blocked autophagic flux. Downregulating Bip significantly blocked the conversion of LC3-I to LC3-II, decreased LC3 puncta formation, and prevented the increase of senescence in PC12 cells. Interestingly, knocking down Bip regulated the expression of p-AMPK, p-AKT and p-s6k induced by Cd. BAPTA, a Bip inhibitor, decreased the expression of p-AMPK and LC3-II, but enhanced neuronal senescence. In addition, we found that siRNA for Bip enhanced GATA4 expression after 6 h Cd exposure in PC12 cells, while rapamycin treatment decreased GATA4 levels induced by 24 h Cd exposure. These results indicate that autophagy degraded GATA4 in a Bip-dependent way. Our findings suggest that autophagy regulated by Bip expression after ER stress suppressed Cd-induced neuronal senescence.

Cadmium-Induced Oxidative Stress: Focus on the Central Nervous System

“…However, it can be assumed that if misfolded proteins are not efficiently degraded, their accumulation contributes to the decrease in cell viability. This suggestion might be in accordance with the results of Wang and colleagues, indicating an endoplasmic reticulum (ER) stress elicited by the increase in the chaperone GRP78 (BiP) that leads to autophagy activation [164]. Indeed, if on the one hand the ER promptly responds to misfolded proteins [165], on the other hand their uncontrolled accumulation in the ER lumen is responsible for the induction of human pathologies, including neurodegenerative disorders [166].…”

Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo

“…1c, d ). In the antigen presentation pathway, the expression of glucose-regulated protein (Bip), a regulator involved in protein translocation into the ER [ 29 ], and TAP1, a transporter associated with antigen presentation [ 30 ], was increased as a dose-dependent manner under 6-OHDA treatment for 24 h (Fig. 1e, f ).…”

“…When protein homeostasis is impaired in neurons, misfolded proteins aggregate in the ER and induce ER stress [ 47 ]. Bip is upregulated and binds aggregated proteins for transportation from the ER to the UPS [ 29 ]. If the UPS and immunoproteasome system are deficient, neurons are more susceptible to apoptosis due to the stress from the accumulation of oxidized proteins [ 8 , 48 ].…”

Trehalose inhibits H2O2-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation

“…GRP78 is an inducible endogenous molecular chaperone within the lumen of ER, which could inhibit ER stress when was over-expressed 47 . Interestingly, it was reported that downregulation of GRP78 significantly suppressed cadmium-induced senescence in PC12 cells via inhibition of autophagy 48 . Notably, we found in this study that trehalose did not up-regulate the expression of GRP78, but inhibited its over-expression induced by H 2 O 2 , which was similar to the effect of NAC or 4-PBA.…”