title: Enhanced lysosomal activity is involved in Bax inhibitor-1-induced regulation of the endoplasmic reticulum (ER) stress response and cell death against ER stress: involvement of vacuolar H+-ATPase (V-ATPase).
abstract: Bax inhibitor-1 (BI-1) is an evolutionarily conserved protein that protects cells against endoplasmic reticulum (ER) stress while also affecting the ER stress response. In this study, we examined BI-1-induced regulation of the ER stress response as well as the control of the protein over cell death under ER stress. In BI-1-overexpressing cells (BI-1 cells), proteasome activity was similar to that of control cells; however, the lysosomal fraction of BI-1 cells showed sensitivity to degradation of BSA. In addition, areas and polygonal lengths of lysosomes were greater in BI-1 cells than in control cells, as assessed by fluorescence and electron microscopy. In BI-1 cells, lysosomal pH was lower than in control cells and lysosomal vacuolar H(+)-ATPase(V-ATPase), a proton pump, was activated, suggesting high H(+) uptake into lysosomes. Even when exposed to ER stress, BI-1 cells maintained high levels of lysosomal activities, including V-ATPase activity. Bafilomycin, a V-ATPase inhibitor, leads to the reversal of BI-1-induced regulation of ER stress response and cell death due to ER stress. In BI-1 knock-out mouse embryo fibroblasts, lysosomal activity and number per cell were relatively lower than in BI-1 wild-type cells. This study suggests that highly maintained lysosomal activity may be one of the mechanisms by which BI-1 exerts its regulatory effects on the ER stress response and cell death.
authors.affiliation: Department of Pharmacology and Cardiovascular Research Institute, Chonbuk National University, Jeonju, Chonbuk 560-180, Korea.
authors.forename: Geum-Hwa
authors.initials: GH
authors.lastname: Lee
authors.forename: Do-Sung
authors.initials: DS
authors.lastname: Kim
authors.forename: Hyung-Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Jung-Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Chin-Ha
authors.initials: CH
authors.lastname: Chung
authors.forename: Taeho
authors.initials: T
authors.lastname: Ahn
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Lim
authors.forename: In-Ki
authors.initials: IK
authors.lastname: Kim
authors.forename: Han-Jung
authors.initials: HJ
authors.lastname: Chae
authors.forename: Hyung-Ryong
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C484209:TMBIM6 protein, human; C490015:Tmbim6 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases