Abstract
Lysosome-related organelles have versatile functions, including protein and lipid degradation, signal transduction and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal-lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system. Here, we describe a previously unknown human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated protein kinase (MAPK) signaling to late endosomes, is crucial for the function of neutrophils, B cells, cytotoxic T cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3' untranslated region (UTR) of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a previously unknown role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Protein Complex 4 / deficiency
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Adaptor Protein Complex 4 / genetics
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Adaptor Protein Complex 4 / metabolism*
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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B-Lymphocytes / ultrastructure
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Base Sequence
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Endosomes / metabolism*
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Endosomes / ultrastructure
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Family Health
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Female
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Genotype
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Granulocyte Colony-Stimulating Factor / pharmacology
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Immunoglobulin D / analysis
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Immunoglobulin M / analysis
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Immunologic Deficiency Syndromes / genetics
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Immunologic Deficiency Syndromes / metabolism*
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Immunologic Deficiency Syndromes / pathology
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Leukocyte Count
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Linkage Disequilibrium
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Luciferases / genetics
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Luciferases / metabolism
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Male
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Melanocytes / metabolism
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Melanocytes / ultrastructure
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Microscopy, Electron, Transmission
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Microscopy, Fluorescence
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Neutrophils / metabolism
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Neutrophils / ultrastructure
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Point Mutation
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / ultrastructure
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / analysis
Substances
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Adaptor Protein Complex 4
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Immunoglobulin D
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Immunoglobulin M
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Recombinant Fusion Proteins
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Granulocyte Colony-Stimulating Factor
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Green Fluorescent Proteins
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Luciferases