Gold Nanoparticles Induce Cell Stress by Interfering with the Cellular Protein Quality Control System

Abstract The cellular protein quality control (PQC) system ensures the intracellular misfolded/unfolded proteins to be detected and eliminated. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the key mechanisms of PQC, which maintain protein homeostasis and ensure cell survival. Here, we show that after internalization by human epithelial cells, gold (Au) nanoparticles (NPs) localized in endoplasmic reticulum (ER) and induced an accumulation of misfolded/unfolded proteins. Au NPs activated UPR, but suppressed ERAD shown by a reduced degradation rate of the ERAD marker CD3-δ-YFP, which triggered ER stress through IRE1-XBP1-Chaperones and PERK-eIF2α-ATF4-CHOP pathways. The Au NP-dependent ER stress consequently induced the intracellular accumulation of ROS, and caused cell apoptosis/death, concomitant to production/release of inflammatory cytokines and chemokines. This study for the first time shows that NPs can interfere with the cellular PQC system by impairing ERAD activity, which in turn initiates a cascade of events leading to cell death and inflammation.