Deficient peptide loading and MHC class II endosomal sorting in a human genetic immunodeficiency disease: the Chediak-Higashi syndrome

被引:119
作者
Faigle, W
Raposo, G
Tenza, D
Pinet, V
Vogt, AB
Kropshofer, H
Fischer, A
de Saint-Basile, G
Amigorena, S
机构
[1] Inst Curie, INSERM, CJF 95 01, Sect Rech, F-75005 Paris, France
[2] Inst Curie, CNRS, UMR144, F-75005 Paris, France
[3] Hop St Eloi, INSERM, U475, F-34295 Montpellier, France
[4] Deutsch Krebsforschungszentrum, Dept Mol Immunol, D-69120 Heidelberg, Germany
[5] Hop Necker Enfants Malad, INSERM, U429, F-75015 Paris, France
关键词
D O I
10.1083/jcb.141.5.1121
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The Chediak-Higashi syndrome (CHS) is a human recessive autosomal disease caused by mutations in a single gene encoding a protein of unknown function, called lysosomal-trafficking regulator. All cells in CHS patients bear enlarged lysosomes, In addition, T- and natural killer cell cytotoxicity is defective in these patients, causing severe immunodeficiencies, We have analyzed major histocompatibility complex class II functions and intracellular transport in Epstein Barr Virus-transformed B cells from CHS patients. Peptide loading onto major histocompatibility complex class II molecules and antigen presentation are strongly delayed these cells, A detailed electron microscopy analy sis of endocytic compartments revealed that only lysosomal multilaminar compartments are enlarged (reaching 1-2 mu m), whereas late multivesicular endosomes have normal size and morphology, In contrast to giant multilaminar compartments that bear most of the usual lysosomal markers in these cells (HLA-DR, HLA-DM, Lamp-1, CD63, etc.), multivesicular late endosomes displayed reduced levels of all these molecules, suggesting a defect in transport from the trans-Golgi network and/or early endosomes into late multivesicular endosomes, Further insight into a possible mechanism of this transport defect came from immunolocalizing the lysosomal trafficking regulator protein, as antibodies directed to a peptide from its COOH terminal domain decorated punctated structures partially aligned along microtubules, These results suggest that the product of the Lyst gene is required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules.
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页码:1121 / 1134
页数:14
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