TY - JOUR
T1 - Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization.
AU - Nylandsted, Jesper
AU - Gyrd-Hansen, Mads
AU - Danielewicz, Agnieszka
AU - Fehrenbacher, Nicole
AU - Lademann, Ulrik
AU - Høyer-Hansen, Maria
AU - Weber, Ekkehard
AU - Multhoff, Gabriele
AU - Rohde, Mikkel
AU - Jäättelä, Marja
N1 - Keywords: Animals; Apoptosis; Caspases; Cathepsins; Cell Membrane Permeability; Cell Survival; HSP70 Heat-Shock Proteins; Hela Cells; Humans; Immunoblotting; Lysosomes; Mice; Microscopy, Immunoelectron; Tumor Cells, Cultured
PY - 2004
Y1 - 2004
N2 - Heat shock protein 70 (Hsp70) is a potent survival protein whose depletion triggers massive caspase-independent tumor cell death. Here, we show that Hsp70 exerts its prosurvival function by inhibiting lysosomal membrane permeabilization. The cell death induced by Hsp70 depletion was preceded by the release of lysosomal enzymes into the cytosol and inhibited by pharmacological inhibitors of lysosomal cysteine proteases. Accordingly, the Hsp70-mediated protection against various death stimuli in Hsp70-expressing human tumor cells as well as in immortalized Hsp70 transgenic murine fibroblasts occurred at the level of the lysosomal permeabilization. On the contrary, Hsp70 failed to inhibit the cytochrome c-induced, apoptosome-dependent caspase activation in vitro and Fas ligand-induced, caspase-dependent apoptosis in immortalized fibroblasts. Immunoelectron microscopy revealed that endosomal and lysosomal membranes of tumor cells contained Hsp70. Permeabilization of purified endo/lysosomes by digitonin failed to release Hsp70, suggesting that it is physically associated with the membranes. Finally, Hsp70 positive lysosomes displayed increased size and resistance against chemical and physical membrane destabilization. These data identify Hsp70 as the first survival protein that functions by inhibiting the death-associated permeabilization of lysosomes.
AB - Heat shock protein 70 (Hsp70) is a potent survival protein whose depletion triggers massive caspase-independent tumor cell death. Here, we show that Hsp70 exerts its prosurvival function by inhibiting lysosomal membrane permeabilization. The cell death induced by Hsp70 depletion was preceded by the release of lysosomal enzymes into the cytosol and inhibited by pharmacological inhibitors of lysosomal cysteine proteases. Accordingly, the Hsp70-mediated protection against various death stimuli in Hsp70-expressing human tumor cells as well as in immortalized Hsp70 transgenic murine fibroblasts occurred at the level of the lysosomal permeabilization. On the contrary, Hsp70 failed to inhibit the cytochrome c-induced, apoptosome-dependent caspase activation in vitro and Fas ligand-induced, caspase-dependent apoptosis in immortalized fibroblasts. Immunoelectron microscopy revealed that endosomal and lysosomal membranes of tumor cells contained Hsp70. Permeabilization of purified endo/lysosomes by digitonin failed to release Hsp70, suggesting that it is physically associated with the membranes. Finally, Hsp70 positive lysosomes displayed increased size and resistance against chemical and physical membrane destabilization. These data identify Hsp70 as the first survival protein that functions by inhibiting the death-associated permeabilization of lysosomes.
U2 - 10.1084/jem.20040531
DO - 10.1084/jem.20040531
M3 - Journal article
C2 - 15314073
SN - 0022-1007
VL - 200
SP - 425
EP - 435
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
IS - 4
ER -