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Palmitoyl protein thioesterase 1 modulates tumor necrosis factor alpha-induced apoptosis.

Abstract : 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.
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Contributor : Marie Francoise Simon Connect in order to contact the contributor
Submitted on : Thursday, August 20, 2009 - 2:44:19 PM
Last modification on : Wednesday, June 1, 2022 - 5:02:02 AM

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Claudine Tardy, Frédérique Sabourdy, Virginie Garcia, Anu Jalanko, Nicole Therville, et al.. Palmitoyl protein thioesterase 1 modulates tumor necrosis factor alpha-induced apoptosis.. Biochimica et Biophysica Acta - Molecular Cell Research, Elsevier, 2009, 1793 (7), pp.1250-8. ⟨10.1016/j.bbamcr.2009.03.007⟩. ⟨inserm-00410418⟩



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