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.
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We thank M. Schlesier (University of Freiburg) for the B-cell phenotyping, I. Sandrock, G. Köhne, F. Noyan, K. Boztug and M. Ballmaier for laboratory support, C. Roifman (Hospital for Sick Children) and R. Gatti (University of California at Los Angeles) for providing control samples on Mennonite families, and E. Ungewickell, C. Baum, J. Bohne, C. Kardinal and H. Holtmann for critical discussions. We thank B. Tümmler (Hannover Medical School), C. Baum (Hannover Medical School) and I. Touw (Erasmus University Medical Center) for reagents, M. Zimmermann for help in statistical evaluations and M. Offterdinger for help in determining subcellular distribution of endosomes. This research was supported by Deutsche Forschungsgemeinschaft grants KFO110 and GR1617/3, BMBF, the Elternverein Krebskranke Kinder Hannover, the Austrian Proteomics Platform (APP, GEN-AU), the Special Research Program “Cell Proliferation and Cell Death in Tumors” (SFB021, Austrian Science Fund) and in part by the intramural research program of the US National Institutes of Health, National Library of Medicine (NLM).
The authors declare no competing financial interests.
Assessment of granzyme B and perforin in cytotoxic T-cells, and TEM of neutrophil granulocytes of patients #10, 12 and 13. (PDF 1673 kb)
Statistical analysis of E. coli lysis assay. Data presented in Fig. 4b were transformed by grouping the samples from HD and genetically corrected cells from patient #5 (black lines). (PDF 61 kb)
Analysis of G-CSF-receptor (G-CSFR) transgenic fibroblast cell lines. (PDF 88 kb)
Statistical analysis of endosome distribution with respect to the distance from the nucleus. (PDF 2523 kb)
Immunophenotyping, in vitro T-cell proliferation, serum immunoglobulin levels and vaccination titers. (PDF 116 kb)
LOD scores and target genes. (PDF 98 kb)
Transcriptional profiling of EBV-transformed B-cell lines. Expression intensities of transcripts in EBV-transformed B-cell lines derived from parents (#1, 2) werecompared to B-cell lines derived from two patients (#12, 13). (PDF 131 kb)
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Bohn, G., Allroth, A., Brandes, G. et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med 13, 38–45 (2007). https://doi.org/10.1038/nm1528
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