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
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Adaptor Protein Complex 4 / deficiency
- Adaptor Protein Complex 4 / genetics
- Adaptor Protein Complex 4 / metabolism*
- B-Lymphocytes / drug effects
- B-Lymphocytes / metabolism
- B-Lymphocytes / ultrastructure
- Base Sequence
- Endosomes / metabolism*
- Endosomes / ultrastructure
- Family Health
- Female
- Genotype
- Granulocyte Colony-Stimulating Factor / pharmacology
- Green Fluorescent Proteins / genetics
- Green Fluorescent Proteins / metabolism
- Humans
- Immunoglobulin D / analysis
- Immunoglobulin M / analysis
- Immunologic Deficiency Syndromes / genetics
- Immunologic Deficiency Syndromes / metabolism*
- Immunologic Deficiency Syndromes / pathology
- Leukocyte Count
- Linkage Disequilibrium
- Luciferases / genetics
- Luciferases / metabolism
- Male
- Melanocytes / metabolism
- Melanocytes / ultrastructure
- Microscopy, Electron, Transmission
- Microscopy, Fluorescence
- Neutrophils / metabolism
- Neutrophils / ultrastructure
- Point Mutation
- Recombinant Fusion Proteins / genetics
- Recombinant Fusion Proteins / metabolism
- T-Lymphocytes, Cytotoxic / metabolism
- T-Lymphocytes, Cytotoxic / ultrastructure
- Tumor Necrosis Factor Receptor Superfamily, Member 7 / analysis
Substances
- Adaptor Protein Complex 4
- Immunoglobulin D
- Immunoglobulin M
- Recombinant Fusion Proteins
- Tumor Necrosis Factor Receptor Superfamily, Member 7
- Granulocyte Colony-Stimulating Factor
- Green Fluorescent Proteins
- Luciferases