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J. Biol. Chem., Vol. 279, Issue 51, 52914-52923, December 17, 2004

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Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

DEFECTIVE RESPONSE IN I-CELL DISEASE FIBROBLASTS^*

Claudine Tardy, Hélène Autefage, Virgine Garcia, Thierry Levade, and Nathalie Andrieu-Abadie

From the INSERM U466, Centre Hospitalier Universitaire de Rangueil, 1 Avenue Jean Poulhès, TSA 50032, 31059 Toulouse cedex 9 France,

Whereas caspases are essential components in apoptosis, other proteases seem to be involved in programmed cell death. This study investigated the role of lysosomal mannose 6-phosphorylated proteins in tumor necrosis factor (TNF)-induced apoptosis. We report that fibroblasts isolated from patients affected with inclusion-cell disease (ICD), having a deficient activity of almost all lysosomal hydrolases, are resistant to the toxic effect of TNF. These mutant cells exhibited a defect in TNF-induced caspase activation, Bid cleavage, and release of cytochrome c. In contrast, TNF-induced p42/p44 MAPK activation and CD54 expression remained unaltered. Human ICD lymphoblasts and fibroblasts derived from mice nullizygous for Igf2 and the two mannose 6-phosphate (M6P) receptors, Mpr300 and Mpr46, which develop an ICD-like phenotype, were also resistant to CD95 ligand and TNF, respectively. Moreover, correction of the lysosomal enzyme defect of ICD fibroblasts, using a medium enriched in M6P-containing proteins, enabled restoration of sensitivity to TNF. This effect was blocked by exogenous M6P but not by cathepsin B or L inhibitors. Altogether, these findings suggest that some M6P-bearing glycoproteins modulate the susceptibility to TNF-induced apoptosis. As a matter of fact, exogenous tripeptidyl peptidase 1, a lysosomal carboxypeptidase, could sensitize ICD fibroblasts to TNF. These observations highlight the hitherto unrecognized role of some mannose 6-phosphorylated proteins such as tripeptidyl peptidase 1 in the apoptotic cascade triggered by TNF.

Received for publication, July 21, 2004 , and in revised form, September 7, 2004.

^* This work was supported in part by grants from INSERM, Université Paul Sabatier, and the Association Vaincre les Maladies Lysosomales. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Ministry of Education and Research fellowship.

To whom correspondence should be addressed. Tel.: 33-561-32-20-60; Fax: 33-561-32-20-84; E-mail: nandrieu{at}toulouse.inserm.fr.

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