title: Deficient peptide loading and MHC class II endosomal sorting in a human genetic immunodeficiency disease: the Chediak-Higashi syndrome.
abstract: 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 analysis of endocytic compartments revealed that only lysosomal multilaminar compartments are enlarged (reaching 1-2 micron), 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.
authors.affiliation: CJF 95-01 INSERM, Institut Curie, 75005 Paris, France.
authors.forename: W
authors.initials: W
authors.lastname: Faigle
authors.forename: G
authors.initials: G
authors.lastname: Raposo
authors.forename: D
authors.initials: D
authors.lastname: Tenza
authors.forename: V
authors.initials: V
authors.lastname: Pinet
authors.forename: A B
authors.initials: AB
authors.lastname: Vogt
authors.forename: H
authors.initials: H
authors.lastname: Kropshofer
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: de Saint-Basile
authors.forename: S
authors.initials: S
authors.lastname: Amigorena
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001692:Biological Transport; D002451:Cell Compartmentation; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D002609:Chediak-Higashi Syndrome / Q000276:immunology*; D011992:Endosomes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D013347:Subcellular Fractions; D033921:Vesicular Transport Proteins
chemical_list: D000949:Histocompatibility Antigens Class II; C102161:LYST protein, human; D008565:Membrane Proteins; D010455:Peptides; D011506:Proteins; D033921:Vesicular Transport Proteins