Intracellular acidification induces apoptosis by stimulating ICE-like protease activity

• Published in: Journal of cell science Vol. 110 ( Pt 5); no. 5; pp. 653 - 661
• Main Authors: Furlong, I J, Ascaso, R, Lopez Rivas, A, Collins, M K
• Format: Journal Article
• Language: English
• Published: England 01.03.1997
• Subjects: Apoptosis; Cell Line; Cysteine Endopeptidases - metabolism; DNA Fragmentation; Enzyme Activation; Flow Cytometry; Humans; Hydrogen-Ion Concentration; Hydrolysis; Interleukin-3 - pharmacology; Poly(ADP-ribose) Polymerases - metabolism
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.110.5.653

ICE-like protease activation and DNA fragmentation are preceded by a decrease in intracellular pH (pHi) during apoptosis in the IL-3 dependent cell line BAF3. Acidification occurs after 7 hours in cells deprived of IL-3 and after 4 hours when cells are treated with etoposide, close to the time of detection of ICE-like protease activity. Increasing extracellular pH reduces ICE-like protease activation and DNA fragmentation. Bcl-2 over-expression both delays acidification and inhibits ICE-like protease activation. Generation of a rapid intracellular pH decrease, using the ionophore nigericin, induces ICE-like protease activation and apoptosis. ZVAD, a cell permeable inhibitor of ICE-like proteases, does not affect acidification but inhibits apoptosis induced by IL-3 removal or nigericin treatment. These data suggest that intracellular acidification triggers apoptosis by directly or indirectly activating ICE-like proteases.