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Blood, 15 July 2006, Vol. 108, No. 2, pp. 493-500.
Prepublished online as a Blood First Edition Paper on March 21, 2006; DOI 10.1182/blood-2005-11-4689.
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Submitted November 28, 2005
Accepted March 2, 2006
Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response
Inga Kollner, Beate Sodeik, Sabine Schreek, Holger Heyn, Nils von Neuhoff, Manuela Germeshausen, Cornelia Zeidler, Martin Kruger, Brigitte Schlegelberger, Karl Welte, and Carmela Beger*
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
Institute of Virology, Hannover Medical School, Hannover, Germany
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
* Corresponding author; email: beger.carmela{at}mh-hannover.de.
Severe congenital (SCN) and cyclic (CyN) neutropenia are sporadic or inherited hematological disorders of myelopoiesis. Heterozygous mutations in the gene encoding neutrophil elastase (ELA2) have been reported in both diseases. Here, we used an inducible system to express a panel of ELA2 mutations and found for almost all mutants disruption of intracellular neutrophil elastase (HNE) protein processing at different levels. This disruption resulted in cytoplasmic accumulation of a non-functional protein, thereby preventing its physiological transport to azurophil granules. Furthermore, the secretory capacity of the mutant proteins was greatly diminished, indicating alteration of the regulated as well as the constitutive pathway. Analyzing primary granulocytes from SCN patients carrying ELA2 mutations, we found an identical pattern of intracellular accumulation of mutant HNE protein in the cytoplasm. Moreover, cells expressing mutant HNE protein exhibited a significant increase in apoptosis, which was associated with upregulation of the master ER chaperone BiP, indicating that disturbance of intracellular trafficking results in activation of the mammalian unfolded protein response.
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