A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14

GEORG BOHN; ANNA ALLROTH; GUDRUN BRANDES; JENS THIEL; ERIK GLOCKER; ALEJANDRO A SCHAFFER; CHOZHAVENDAN RATHINAM; NICOLE TAUB; DAVID TEIS; CORNELIA ZEIDLER; RICARDO A. DEWEY; ROBERT GEFFERS; JAN BUER; LUKAS HUBER; KARL WELTE; BODO GRIMBACHER; CHRISTOPH KLEIN

NATURE MEDICINE.

Nature America Inc,

Lugar: New York; Año: 2007 vol. 13 p. 38 - 45

1078-8956

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. 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. 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.