title: Arsenite-induced autophagy is associated with proteotoxicity in human lymphoblastoid cells.
abstract: Epidemiological studies of arsenic-exposed populations have provided evidence that arsenic exposure in humans is associated with immunosuppression. Previously, we have reported that arsenite-induced toxicity is associated with the induction of autophagy in human lymphoblastoid cell lines (LCL). Autophagy is a cellular process that functions in the degradation of damaged cellular components, including protein aggregates formed by misfolded or damaged proteins. Accumulation of misfolded or damaged proteins in the endoplasmic reticulum (ER) lumen causes ER stress and activates the unfolded protein response (UPR). In an effort to investigate the mechanism of autophagy induction by arsenite in the LCL model, we examined the potential contribution of ER stress and activation of the UPR. LCL exposed to sodium arsenite for 8-days induced expression of UPR-activated genes, including CHOP and GRP78, at the RNA and the protein level. Evidence for activation of the three arms of the UPR was observed. The arsenite-induced activation of the UPR was associated with an accumulation of protein aggregates containing p62 and LC3, proteins with established roles in the sequestration and autophagic clearance of protein aggregates. Taken together, these data provide evidence that arsenite-induced autophagy is associated with the generation of ER stress, activation of the UPR, and formation of protein aggregates that may be targeted to the lysosome for degradation.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Bolt
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Samantha
authors.initials: S
authors.lastname: Pacheco
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
mesh_terms: D000588:Amines; D000704:Analysis of Variance; D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D008208:Lymphatic System / Q000166:cytology* / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D046228:Microarray Analysis; D020543:Proteome / Q000187:drug effects*; D057165:Proteostasis Deficiencies / Q000139:chemically induced* / Q000503:physiopathology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000588:Amines; D018053:Arsenites; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007202:Indicators and Reagents; D020543:Proteome; C493330:Red DND-99; D012313:RNA; C015001:arsenite