Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) are sporadic or inherited hematologic disorders of myelopoiesis. Heterozygous mutations in the gene encoding neutrophil elastase (ELA2) have been reported in both diseases. 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 nonfunctional protein, thereby preventing its physiologic transport to azurophil granules. Furthermore, the secretory capacity of the mutant proteins was greatly diminished, indicating alteration of the regulated and the constitutive pathways. Through analysis of 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 associated with up-regulation 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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PMID:Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. 1655 67

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis. However, the mechanisms by which these mutations disrupt granulopoiesis are unclear. We hypothesize that the ELA2 mutations result in the production of misfolded NE protein, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Expression of mutant NE but not wild-type NE strongly induced BiP/GRP78 mRNA expression and XBP1 mRNA splicing, 2 classic markers of the UPR. The magnitude of UPR activation by a specific ELA2 mutation correlated with its associated clinical phenotype. Consistent with the UPR model, expression of mutant NE in primary human granulocytic precursors increased expression of CHOP (DDITS) and induced apoptosis in a protease-independent fashion. Most strikingly, UPR activation and decreased NE protein expression were detected in primary granulocytic precursors from SCN patients. Collectively, these data provide strong support for a UPR model of SCN disease pathogenesis and place SCN in a growing list of human diseases caused by misfolded proteins.
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PMID:Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. 1776 33

Deficiency in neutrophils (neutropenia) caused by mutations in neutrophil elastase (NE, ELA2) has been extensively investigated. Monocytes and neutrophils are derived from a common myeloid progenitor; therefore, ELA2 mutations can also influence monocyte development. These effects have not been well described. In this study, we used the human monocytic THP-1, to carry the human wild-type and G185R mutant ELA2 gene. Growth, death, differentiation and BiP expression were evaluated in the two stable cell lines and in the wild-type THP-1 cells. Exogenous wild-type ELA2 markedly increased THP-1 differentiation, whereas G185R ELA2 was incompetent to promote THP-1 differentiation in response to all-trans retinoic acid (ATRA). Indeed, during differentiation induced by ATRA, G185R cell line showed significant cell death. Also, up-regulated BiP expression accompanied cell death in the G185R cells, suggesting that the overexpression of G185R elastase increases apoptosis through an unfolded protein response. The G185R cells treated with lithium chloride (LiCl; a Wnt signalling activator) displayed higher BiP expression but similar cell viability compared with THP1 and HNEwt/THP1 cells treated with LiCl. This suggested that Wnt signalling might increase cellular tolerance to endoplasmic reticulum stress, enabling mutant monocyte survival.
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PMID:The neutrophil elastase mutant affects viability and differentiation of the human monocytic THP-1 cell. 2299 20