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)

• Published in: The Journal of biological chemistry 2011-07, Vol.286 (28), p.24743-24753
• Main Authors: Lee, Geum-Hwa, Kim, Do-Sung, Kim, Hyung-Tae, Lee, Jung-Wook, Chung, Chin-Ha, Ahn, Taeho, Lim, Jung Min, Kim, In-Ki, Chae, Han-Jung, Kim, Hyung-Ryong
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell Death - physiology; Cell Line, Tumor; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Endoplasmic Reticulum Stress - physiology; Enzyme Inhibitors - pharmacology; Fibroblasts - cytology; Fibroblasts - metabolism; Humans; Hydrogen-Ion Concentration; Lysosomes - genetics; Lysosomes - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Vacuolar Proton-Translocating ATPases - antagonists & inhibitors; Vacuolar Proton-Translocating ATPases - genetics; Vacuolar Proton-Translocating ATPases - metabolism
• ISSN: 1083-351X
• DOI: 10.1074/jbc.M110.167734

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.