PMID- 19345705 OWN - NLM STAT- MEDLINE DCOM- 20090818 LR - 20231213 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1793 IP - 7 DP - 2009 Jul TI - Palmitoyl protein thioesterase 1 modulates tumor necrosis factor alpha-induced apoptosis. PG - 1250-8 LID - 10.1016/j.bbamcr.2009.03.007 [doi] AB - Induction 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. FAU - Tardy, Claudine AU - Tardy C AD - INSERM, U858, Toulouse, France. FAU - Sabourdy, Frederique AU - Sabourdy F FAU - Garcia, Virginie AU - Garcia V FAU - Jalanko, Anu AU - Jalanko A FAU - Therville, Nicole AU - Therville N FAU - Levade, Thierry AU - Levade T FAU - Andrieu-Abadie, Nathalie AU - Andrieu-Abadie N LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20090405 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (CLN3 protein, mouse) RN - 0 (Cln5 protein, mouse) RN - 0 (Lysosomal Membrane Proteins) RN - 0 (Membrane Glycoproteins) RN - 0 (Membrane Proteins) RN - 0 (Molecular Chaperones) RN - 0 (NF-kappa B) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (TNF-Related Apoptosis-Inducing Ligand) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (PPT1 protein, human) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Blotting, Western MH - Cell Transformation, Neoplastic MH - Fibroblasts/cytology/drug effects/metabolism MH - Flow Cytometry MH - Humans MH - Lysosomal Membrane Proteins MH - Membrane Glycoproteins/*physiology MH - Membrane Proteins/genetics/*metabolism MH - Mice MH - Mice, Knockout MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Molecular Chaperones/*physiology MH - NF-kappa B/metabolism MH - Neuronal Ceroid-Lipofuscinoses/enzymology/pathology MH - Receptors, Tumor Necrosis Factor, Type I/metabolism MH - Skin/cytology/drug effects/metabolism MH - TNF-Related Apoptosis-Inducing Ligand/metabolism MH - Thiolester Hydrolases/*physiology MH - Tumor Necrosis Factor-alpha/*pharmacology EDAT- 2009/04/07 09:00 MHDA- 2009/08/19 09:00 CRDT- 2009/04/07 09:00 PHST- 2008/11/26 00:00 [received] PHST- 2009/03/19 00:00 [revised] PHST- 2009/03/23 00:00 [accepted] PHST- 2009/04/07 09:00 [entrez] PHST- 2009/04/07 09:00 [pubmed] PHST- 2009/08/19 09:00 [medline] AID - S0167-4889(09)00081-0 [pii] AID - 10.1016/j.bbamcr.2009.03.007 [doi] PST - ppublish SO - Biochim Biophys Acta. 2009 Jul;1793(7):1250-8. doi: 10.1016/j.bbamcr.2009.03.007. Epub 2009 Apr 5.