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Palmitoyl protein thioesterase 1 modulates tumor necrosis factor alpha-induced apoptosis Tardy C; Sabourdy F; Garcia V; Jalanko A; Therville N; Levade T; Andrieu-Abadie NBiochim Biophys Acta 2009[Jul]; 1793 (7): 1250-8Induction of apoptosis by TNF has recently been shown to implicate proteases from lysosomal origin, the cathepsins. Here, we investigated the role in apoptosis of palmitoyl protein thioesterase 1 (PPT1), another lysosomal enzyme that depalmitoylates proteins. We show that transformed fibroblasts derived from patients with the infantile form of neuronal ceroid lipofuscinosis (INCL), a neurodegenerative disease due to deficient activity of PPT1, are partially resistant to TNF-induced cell death (57-75% cell viability vs. 15-30% for control fibroblasts). TNF-initiated proteolytic cleavage of caspase-8, Bid and caspase-3, as well as cytochrome c release was strongly attenuated in INCL fibroblasts as compared to control cells. Noteworthy, activation of p42/p44 mitogen-activated protein kinase and of transcription factor NF-kappaB by TNF, and induction of cell death by staurosporine or chemotherapeutic drugs in INCL cells were unaffected by PPT1 deficiency. Resistance to TNF-induced apoptosis was also observed in embryonic fibroblasts derived from Ppt1/Cln1-deficient mice but not from mice with a targeted deletion of Cln3 or Cln5. Finally, reconstitution of PPT1 activity in mutant cells was accompanied by resensitization to TNF-induced caspase activation and toxicity. These observations emphasize for the first time the role of PPT1 and, likely, protein depalmitoylation in the regulation of TNF-induced apoptosis.|Animals[MESH]|Apoptosis/*drug effects[MESH]|Blotting, Western[MESH]|Cell Transformation, Neoplastic[MESH]|Fibroblasts/cytology/drug effects/metabolism[MESH]|Flow Cytometry[MESH]|Humans[MESH]|Lysosomal Membrane Proteins[MESH]|Membrane Glycoproteins/*physiology[MESH]|Membrane Proteins/genetics/*metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Mitogen-Activated Protein Kinase 1/metabolism[MESH]|Mitogen-Activated Protein Kinase 3/metabolism[MESH]|Molecular Chaperones/*physiology[MESH]|NF-kappa B/metabolism[MESH]|Neuronal Ceroid-Lipofuscinoses/enzymology/pathology[MESH]|Receptors, Tumor Necrosis Factor, Type I/metabolism[MESH]|Skin/cytology/drug effects/metabolism[MESH]|TNF-Related Apoptosis-Inducing Ligand/metabolism[MESH]|Thiolester Hydrolases/*physiology[MESH]|Tumor Necrosis Factor-alpha/*pharmacology[MESH] |
