ELANE mutant-specific activation of different UPR pathways in congenital neutropenia.

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_C181del (NP_001963.1) and CN/CyN-shared p.S126L (NP_001963.1) ELANE mutants. We found that transduction of haematopoietic cells with p.C71R, but not with p.V174_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.

• Authors: Rainer Nustede, Maksim Klimiankou, Olga Klimenkova, Inna Kuznetsova, Cornelia Zeidler, Karl Welte, Julia Skokowa
• Journal: British journal of haematology (Br J Haematol) Vol. 172 Issue 2 Pg. 219-27 (Jan 2016) ISSN: 1365-2141 [Electronic] England
• PMID: 26567890 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons Ltd.

Chemical References

• ATF4 protein, human
• ATF6 protein, human
• Activating Transcription Factor 6
• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• RNA, Messenger
• Activating Transcription Factor 4
• EIF2AK3 protein, human
• eIF-2 Kinase
• Leukocyte Elastase

Topics

• 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
• Leukocyte Elastase (genetics)
• Mutation
• Myeloid Cells (metabolism)
• Neutropenia (congenital, genetics, metabolism)
• RNA, Messenger (genetics)
• Unfolded Protein Response (genetics)
• eIF-2 Kinase (biosynthesis)