Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells.
Participation of diverse organelles in the intracellular signalling that follows CD95/Fas receptor ligation encompasses a series of subcellular changes that are mandatory for, or even bolster, the apoptotic cascade. In the present study, we analysed the role of endocytosis in the propagation of cell death signalling after CD95/Fas engagement in type II cells (CEM cells). We show that this receptor-ligand interaction triggers endocytosis independently of any caspase activation. This FasL (Fas ligand)-induced endocytosis also leads to an early and directional 'movement' of endocytic vesicles towards the mitochondrial compartment. In turn, this cross-talk between endosomal and mitochondrial compartments was followed by the loss of the mitochondrial membrane potential and apoptosis execution. This cell remodelling was absent in receptor-independent cell death, such as that induced by the mitochondriotropic drug staurosporine, and in a CEM cell line selected for its multidrug resistance (CEM VBL100). In these cells a reduced FasL (Fas ligand)-induced endocytosis and a reduced organelle cross-talk corresponded to a reduced apoptosis. Altogether, these findings suggest a key role of endocytosis in the propagation and amplification of the CD95/Fas-activated signalling leading to type II cell demise.
Matarrese
Paola
P
Department of Drug Research and Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanità, viale Regina Elena 299, 00161 Rome, Italy.
Manganelli
Valeria
V
Garofalo
Tina
T
Tinari
Antonella
A
Gambardella
Lucrezia
L
Ndebele
Kenneth
K
Khosravi-Far
Roya
R
Sorice
Maurizio
M
Esposti
Mauro Degli
MD
Malorni
Walter
W
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D053222:Fas Ligand Protein / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008985:Monensin / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; D019014:fas Receptor; D008985:Monensin; D020782:Matrix Metalloproteinases; D019311:Staurosporine