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ELANE mutant-specific activation of different UPR pathways in congenital neutropenia.
- Source :
-
British journal of haematology [Br J Haematol] 2016 Jan; Vol. 172 (2), pp. 219-27. Date of Electronic Publication: 2015 Nov 16. - Publication Year :
- 2016
-
Abstract
- A number of studies have demonstrated induction of the unfolded protein response (UPR) in patients with severe congenital neutropenia (CN) harbouring mutations of ELANE, encoding neutrophil elastase. Why UPR is not activated in patients with cyclic neutropenia (CyN) carrying the same ELANE mutations is unclear. We evaluated the effects of ELANE mutants on UPR induction in myeloid cells from CN and CyN patients, and analysed whether additional CN-specific defects contribute to the differences in UPR induction between CN and CyN patients harbouring identical ELANE mutations. We investigated CN-specific p.C71R and p.V174&#95;C181del (NP&#95;001963.1) and CN/CyN-shared p.S126L (NP&#95;001963.1) ELANE mutants. We found that transduction of haematopoietic cells with p.C71R, but not with p.V174&#95;C181del or p.S126L ELANE mutants induced expression of ATF6, and the ATF6 target genes PPP1R15A, DDIT3 and HSPA5. Recently, we found that levels of secretory leucocyte protease inhibitor (SLPI), a natural ELANE inhibitor, are diminished in myeloid cells from CN patients, but not CyN patients. Combined knockdown of SLPI by shRNA and transduction of ELANE p.S126L in myeloid cells led to elevated levels of ATF6, PPP1R15A and HSPA5 RNA, suggesting that normal levels of SLPI in CyN patients might protect them from the UPR induced by mutant ELANE. In summary, different ELANE mutants have different effects on UPR activation, and SLPI regulates the extent of ELANE-triggered UPR.<br /> (© 2015 John Wiley & Sons Ltd.)
- Subjects :
- Activating Transcription Factor 4 biosynthesis
Activating Transcription Factor 6 biosynthesis
CCAAT-Enhancer-Binding Proteins physiology
Case-Control Studies
Congenital Bone Marrow Failure Syndromes
Endoplasmic Reticulum Chaperone BiP
Gene Expression Regulation physiology
Humans
Myeloid Cells metabolism
Neutropenia genetics
Neutropenia metabolism
RNA, Messenger genetics
eIF-2 Kinase biosynthesis
Leukocyte Elastase genetics
Mutation
Neutropenia congenital
Unfolded Protein Response genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 172
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 26567890
- Full Text :
- https://doi.org/10.1111/bjh.13823